Danazol

Not to be confused with Danabol.

Danazol

Clinical data
Trade names	Danatrol, Danocrine, Danol, Danoval, others
Other names	WIN-17757; 2,3-Isoxazolethisterone; 2,3-Isoxazol-17α-ethynyltestosterone; 17α-Ethynyl-17β-hydroxyandrost-4-en-[2,3-d]isoxazole
AHFS/Drugs.com	Monograph
MedlinePlus	a682599
Pregnancy category	AU:D
Routes of administration	By mouth
Drug class	Androgen; Anabolic steroid; Progestogen; Progestin; Antigonadotropin; Steroidogenesis inhibitor; Antiestrogen
ATC code	G03XA01 ( WHO )
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Saturable with dosage, higher with food intake [1]
Protein binding	To albumin, SHBG Tooltip sex hormone-binding globulin, CBG Tooltip corticosteroid-binding globulin [2] [3] [4]
Metabolism	Liver (CYP3A4) [5] [6]
Metabolites	• 2-OHM-Ethisterone [6] • Ethisterone [7] [8]
Elimination half-life	Acute: 3–10 hours [5] [1] Chronic: 24–26 hours [5]
Excretion	Urine, feces [5] [1]
Identifiers
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
CAS Number	17230-88-5  Y
PubChem CID	28417
IUPHAR/BPS	6942
DrugBank	DB01406  Y
ChemSpider	26436  Y
UNII	N29QWW3BUO
KEGG	D00289  Y
ChEBI	CHEBI:4315  Y
ChEMBL	ChEMBL1479  Y
CompTox Dashboard (EPA)	DTXSID2022880
ECHA InfoCard	100.037.503
Chemical and physical data
Formula	C22H27NO2
Molar mass	337.463 g·mol−1
3D model (JSmol)	Interactive image
SMILES C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=Cc5oncc5C[C@]4(C)[C@H]3CC[C@@]21C
InChI 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 Y Key:POZRVZJJTULAOH-LHZXLZLDSA-N Y
(verify)

Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. ^{[5] [1] [9] [10] [11]} It is taken by mouth. ^[1]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening. ^{[1] [12]} 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. ^{[4] [13] [14] [15]}

Danazol was discovered in 1963 and was introduced for medical use in 1971. ^{[13] [16] [17] [18]} 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. ^[3]

Medical uses

Danazol is used primarily in the treatment of endometriosis. It has also been used – mostly off-label – for other indications, namely in the management of menorrhagia, fibrocystic breast disease, immune thrombocytopenic purpura, premenstrual syndrome, breast pain, and hereditary angioedema. ^[19] Although not currently a standard treatment for menorrhagia, danazol demonstrated significant relief in young women with menorrhagia in a study, and, because of a lack of a significant adverse effects, it was proposed as an alternative treatment. ^[20] Danazol appears to be useful in the treatment of systemic lupus erythematosus. ^[21]

Available forms

Danazol comes in the form of 50, 100, and 200 mg oral capsules. ^[1] 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. ^[1]

Contraindications

Danazol is contraindicated during pregnancy because it has the potential to virilize female fetuses. Women taking danazol should practice effective contraception to prevent pregnancy if sexually active. ^[22]

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. ^[23]

Side effects

See also: Anabolic steroid § Adverse effects

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice, ^[3] or adverse blood lipid profiles. ^[22] In addition, breast atrophy and decreased breast size may occur. ^[3] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes. ^[22]

The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer. ^[24] 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. ^[25]

Pharmacology

Pharmacodynamics

Danazol possesses a complex pharmacology, with multiple mechanisms of action. ^{[4] [13] [14]} These include direct binding to and activation of sex hormone receptors, direct inhibition of enzymes involved in steroidogenesis, and direct binding to and occupation of steroid hormone carrier proteins and consequent displacement of steroid hormones from these proteins. ^{[3] [4] [13] [14]} The drug is characterized as a weak androgen and anabolic, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen. ^{[13] [15]}

Modulation of steroid hormone receptors

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). ^{[3] [4]} As an androgen, danazol is described as weak, being about 200-fold less potent than testosterone in bioassays. ^[15] 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). ^[4] 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. ^[4] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid. ^[4] In accordance, it can suppress the immune system at sufficient dosages. ^{[4] [13] [15]}

Relative affinities (%) of danazol and metabolites

Steroid	PR Tooltip Progesterone receptor	AR Tooltip Androgen receptor	ER Tooltip Estrogen receptor	GR Tooltip Glucocorticoid receptor	MR Tooltip Mineralocorticoid receptor	SHBG Tooltip 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 progesterone for the PR Tooltip progesterone receptor, testosterone (c = DHT) for the AR Tooltip androgen receptor, cortisol for the GR Tooltip glucocorticoid receptor (b = dexamethasone), aldosterone for the MR Tooltip mineralocorticoid receptor, DHT for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip corticosteroid-binding globulin. a = 1-hour incubation time (4 hours is standard for this assay; may affect affinity value). Sources: [26] [27] [28] [29] [30] [31]

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: [3] [4]

Inhibition of steroidogenesis enzymes

Danazol has been found to act as an inhibitor, to varying extents, of a variety of steroidogenic enzymes, including cholesterol side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ^5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase. ^[4] It has also been found to be a weak inhibitor of steroid sulfatase (K_i = 2.3–8.2 μM), the enzyme that converts DHEA-S Tooltip dehydroepiandrosterone sulfate into DHEA Tooltip dehydroepiandrosterone and estrone sulfate into estrone (which can then respectively be transformed into estrone (with androstenedione as an intermediate) and estradiol), ^[32] though another study reported its inhibition to be potent and potentially clinically relevant. ^[33] 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. ^[32]

In accordance with its steroidogenesis inhibition, clinical studies have demonstrated that danazol directly and markedly inhibits adrenal, ovarian, and testicular steroidogenesis in vivo . ^[4] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited. ^[4]

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: [4]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women. ^[4]

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: [4]

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. ^{[3] [4]} Binding of danazol to SHBG is considered to be more important clinically. ^[4] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol. ^{[3] [4]} The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol. ^[4]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol. ^{[4] [34]} 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. ^{[4] [34]} 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. ^{[3] [4]} 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). ^[35] 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). ^[15]

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. ^[36] As such, most of the occupation of SHBG by danazol may actually be due to this metabolite. ^[36]

Antigonadotropic activity

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects. ^[4] 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), ^[37] the drug prevents the mid-cycle surge in the levels of these hormones during the menstrual cycle. ^{[3] [15] [22] [38] [39]} By doing this, it suppresses increases in estrogen and progesterone levels at this time and prevents ovulation. ^{[15] [22] [38] [39]}

Mechanism of action in endometriosis

Because danazol reduces estrogen production and levels, ^[37] it has functional antiestrogenic properties. ^[40] The combination of its antiestrogenic, androgenic, and progestogenic or antiprogestogenic actions cause atrophy of the endometrium, which alleviates the symptoms of endometriosis. ^{[3] [4] [15] [37] [41]}

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. ^[42] However, even at the highest dosage assessed (800 mg/day), spermatogenesis remained unaffected. ^[42]

Pharmacokinetics

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. ^[1] 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. ^[1] Similar findings were observed for chronic administration. ^[1] 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. ^[1] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours. ^[1] Steady-state levels of danazol are achieved after 6 days of twice-daily administration. ^[1] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments. ^[1] The volume of distribution of danazol is 3.4 L. ^[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG. ^{[2] [3] [4]}

Danazol is metabolized in the liver by enzymes such as CYP3A4. ^{[5] [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. ^{[5] [1]} 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] [1] [7] [43]} and other, minor metabolites include δ²-hydroxymethylethisterone, 6β-hydroxy-2-hydroxymethylethisterone, and δ¹-6β-hydroxy-2-hydroxymethylethisterone. ^[44] At least 10 different metabolites have been identified. ^[1] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone. ^[1]

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 synthetic androstane steroid and a derivative of testosterone and ethisterone (17α-ethynyltestosterone). ^{[9] [10] [42]} It is specifically the derivative of ethisterone where the C3 ketone is replaced with a 2,3-isoxazole moiety (i.e., an isoxazole ring is fused to the A ring at the C2 and C3 positions). ^{[6] [13]} Ethisterone is a weak progestin with weak androgenic activity. ^[45]

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. ^{[16] [17]} 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. ^{[13] [18]}

Society and culture

Generic names

Danazol is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, DCIT Tooltip Denominazione Comune Italiana, and JAN Tooltip Japanese Accepted Name. ^{[5] [9] [10] [11] [46]} It is also known by its developmental code name WIN-17757. ^{[5] [9] [10] [11] [46]}

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. ^{[5] [9] [10] [11] [46]}

Availability

Danazol is available in the United States, Europe, and widely elsewhere throughout the world. ^{[5] [10] [46]}

Research

Danazol has been studied in the treatment of breast cancer in women, but produced relatively low response rates of about 15 to 20%. ^{[47] [48]}

Low-dose danazol has been investigated in the treatment of diabetic macular edema in a phase III clinical trial. ^{[49] [50]}

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. ^[51]

References

1. "Danocrine Brand of Danazol Capsules, USP" (PDF). Sanofi-Aventis U.S. LLC. U.S. Food and Drug Administration.
2. Griffin JP, D'Arcy PF (17 November 1997). A Manual of Adverse Drug Interactions. Elsevier. pp. 194–. ISBN   978-0-08-052583-9.
3. Nieschlag E, Behre HM, Nieschlag S (13 January 2010). Andrology: Male Reproductive Health and Dysfunction. Springer Science & Business Media. pp. 426–428. ISBN   978-3-540-78355-8.
4. Thomas EJ, Rock J (6 December 2012). Modern Approaches to Endometriosis. Springer Science & Business Media. pp. 239–256. ISBN   978-94-011-3864-2.
5. Brayfield A, ed. (30 October 2013). "Danazol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 1 April 2014.
6. Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1361–. ISBN   978-1-60913-345-0.
7. Dörwald FZ (4 February 2013). Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds. John Wiley & Sons. pp. 485–. ISBN   978-3-527-64565-7.
8. Kurman RJ (17 April 2013). Blaustein's Pathology of the Female Genital Tract. Springer Science & Business Media. pp. 390–. ISBN   978-1-4757-3889-6.
9. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 345–. ISBN   978-1-4757-2085-3.
10. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 293–. ISBN   978-3-88763-075-1.
11. Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 91–. ISBN   978-94-011-4439-1.
12. 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. PMID   17943735.
13. Jones HW, Rock JA (10 July 2015). Te Linde's Operative Gynecology. Wolters Kluwer Health. pp. 1327–1330. ISBN   978-1-4963-1521-2.
14. Lupulescu A (24 October 1990). Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 103–. ISBN   978-0-8493-5973-6.
15. Altchek A, Deligdisch L, Kase N (4 September 2003). Diagnosis and Management of Ovarian Disorders. Academic Press. pp. 376–. ISBN   978-0-08-049451-7.
16. Singh H, Kapoor VK, Paul D (1979). "Heterosteroids and drug research". Progress in Medicinal Chemistry. 16: 35–149. doi:10.1016/s0079-6468(08)70187-5. ISBN   9780720406672. PMID   95596. pp. 126, note 158, 130, notes 1513, 2369, citing Neumann HC, Potts GO, Ryan WT, Stonner FW (September 1970). "Steroidal heterocycles. 13. 4alpha,5-Epoxy-5alpha-androst-2-eno[2,3-d]isoxazoles and related compounds". Journal of Medicinal Chemistry. 13 (5): 948–951. doi:10.1021/jm00299a034. PMID   4318768.
17. Elias AN, Gwinup G (1 January 1983). Hirsutism. Praeger. p. 70. ISBN   9780030603211.
18. Dmowski WP, Scholer HF, Mahesh VB, Greenblatt RB (January 1971). "Danazol--a synthetic steroid derivative with interesting physiologic properties". Fertility and Sterility. 22 (1): 9–18. doi: 10.1016/S0015-0282(16)37981-X . PMID   5538758.
19. Flower R, Rang HP, Dale MM, Ritter JM (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN   978-0-443-06911-6.
20. Luisi S, Razzi S, Lazzeri L, Bocchi C, Severi FM, Petraglia F (October 2009). "Efficacy of vaginal danazol treatment in women with menorrhagia during fertile age". Fertility and Sterility. 92 (4): 1351–1354. doi: 10.1016/j.fertnstert.2008.08.017 . PMID   18930222.
21. 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. PMID   20541792.
22. Hoffman 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. ISBN   9780071716727. Archived from the original on March 28, 2013.
23. "Danazol: MedlinePlus Drug Information". medlineplus.gov. Retrieved 2018-11-07.
24. 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. PMID   14613992.
25. Velazquez I, Alter BP (November 2004). "Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions". American Journal of Hematology. 77 (3): 257–267. doi: 10.1002/ajh.20183 . PMID   15495253. S2CID   42150333.
26. 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. PMID   8136304. S2CID   21336380.
27. Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Research. 38 (11 Pt 2): 4186–4198. PMID   359134.
28. Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP (January 1980). "Steroid flexibility and receptor specificity". Journal of Steroid Biochemistry. 13 (1): 45–59. doi:10.1016/0022-4731(80)90112-0. PMID   7382482.
29. 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. PMID   7195405.
30. 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. PMID   7197818. S2CID   2702353.
31. 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. PMID   20814732. S2CID   24785562.
32. Shields-Botella J, Chetrite G, Meschi S, Pasqualini JR (January 2005). "Effect of nomegestrol acetate on estrogen biosynthesis and transformation in MCF-7 and T47-D breast cancer cells". The Journal of Steroid Biochemistry and Molecular Biology. 93 (1): 1–13. doi: 10.1016/j.jsbmb.2004.11.004 . PMID   15748827. S2CID   25273633.
33. 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. PMID   6238495. S2CID   45817485.
34. Helms RA, Quan DJ (2006). Textbook of Therapeutics: Drug and Disease Management. Lippincott Williams & Wilkins. pp. 383–. ISBN   978-0-7817-5734-8.
35. Wakelin SH, Maibach HI, Archer CB (21 May 2015). Handbook of Systemic Drug Treatment in Dermatology, Second Edition. CRC Press. pp. 23–. ISBN   978-1-4822-2286-9.
36. Westphal U (6 December 2012). Steroid-Protein Interactions II. Springer Science & Business Media. pp. 256–. ISBN   978-3-642-82486-9.
37. Tollison CD, Satterthwaite JR, Tollison JW (January 2002). Practical Pain Management. Lippincott Williams & Wilkins. pp. 479–. ISBN   978-0-7817-3160-7.
38. Floyd WS (1980). "Danazol: endocrine and endometrial effects". International Journal of Fertility. 25 (1): 75–80. PMID   6104649.
39. Katzung B (2012). Basic & Clinical Pharmacology (12 ed.). McGraw Hill. p. 732. ISBN   978-0-07-176401-8.
40. Taylor RB (25 September 1998). Taylor's Family Medicine Review. Springer New York. p. 221. ISBN   978-0-387-98569-5.
41. 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.
42. Bruneteau DW, Bernard I, Greenblatt RB (1974). "[Clinical studies with a new antigonadotropin: Danazol]". Gynécologie (in French). 25 (1): 41–45. PMID   4422449. Archived from the original on 2018-09-04. Retrieved 2018-03-04. Danazol (2-3-isoxazol-17alpha-ethinyl-testosterone)
43. Mozayani A, Raymon L (18 September 2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science & Business Media. pp. 646–. ISBN   978-1-61779-222-9.
44. "PRODUCT INFORMATION" (PDF). Therapeutic Goods Administration . June 21, 2005.
45. Kadam SS (July 2007). Principles of Medicinal Chemistry. Vol. II. Pragati Books Pvt. Ltd. pp. 364–. ISBN   978-81-85790-03-9.
46. "Danazol : Uses, Dosage, Side Effects".
47. Lupulescu A (24 October 1990). Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 48–. ISBN   978-0-8493-5973-6.
48. Pisters PW, Brennan MF (21 November 2013). Protein and Amino Acid Metabolism in Cancer Cachexia. Springer Science & Business Media. pp. 260–. ISBN   978-3-662-22346-8.
49. "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.
50. "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.
51. Townsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, et al. (May 2016). "Danazol Treatment for Telomere Diseases". The New England Journal of Medicine. 374 (20): 1922–1931. doi:10.1056/NEJMoa1515319. PMC   4968696 . PMID   27192671.

Further reading

• Dmowski WP (March 1979). "Endocrine properties and clinical application of danazol". Fertility and Sterility. 31 (3): 237–251. doi:10.1016/S0015-0282(16)43869-0. PMID   374128.
• Fraser IS (April 1979). "Danazol--a steroid with a unique combination of actions". Scottish Medical Journal. 24 (2): 147–150. doi:10.1177/003693307902400209. PMID   386503. S2CID   11557840.
• Potts GO, Schane HP, Edelson J (May 1980). "Pharmacology and pharmacokinetics of danazol". Drugs. 19 (5): 321–330. doi:10.2165/00003495-198019050-00001. PMID   6993179. S2CID   39178416.
• Jenkin G (May 1980). "Review: The mechanism of action of danazol, a novel steroid derivative". The Australian & New Zealand Journal of Obstetrics & Gynaecology. 20 (2): 113–118. doi:10.1111/j.1479-828X.1980.tb00107.x. PMID   6998453. S2CID   29935606.
• Barbieri RL, Ryan KJ (October 1981). "Danazol: endocrine pharmacology and therapeutic applications". American Journal of Obstetrics and Gynecology. 141 (4): 453–463. doi:10.1016/0002-9378(81)90611-6. PMID   7025640.
• 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. PMID   2404115.
• Barbieri RL (1990). "Danazol: molecular, endocrine, and clinical pharmacology". Progress in Clinical and Biological Research. 323: 241–252. PMID   2406750.
• 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. PMID   17253444.
• Beaumont H, Augood C, Duckitt K, Lethaby A (July 2007). "Danazol for heavy menstrual bleeding". The Cochrane Database of Systematic Reviews. 2007 (3): CD001017. doi:10.1002/14651858.CD001017.pub2. PMC   7028060 . PMID   17636649.
• Selak V, Farquhar C, Prentice A, Singla A (October 2007). "Danazol for pelvic pain associated with endometriosis". The Cochrane Database of Systematic Reviews (4): CD000068. doi:10.1002/14651858.CD000068.pub2. PMID   17943735.
• 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. PMID   18387221.
• Ke LQ, Yang K, Li J, Li CM (July 2009). "Danazol for uterine fibroids". The Cochrane Database of Systematic Reviews. 2009 (3): CD007692. doi:10.1002/14651858.CD007692.pub2. PMC   7188078 . PMID   19588442.
• 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. PMID   20541792.