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.
The use of danazol is limited by virilization such as acne, hirsutism, and voice deepening.
Danazol was discovered in 1963 and was introduced for medical use in 1971.
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,
mastodynia, and hereditary angioedema.
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.
Danazol appears to be useful in the treatment of systemic lupus erythematosus.
Available forms
Danazol comes in the form of 50, 100, and 200 mg oral capsules.
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.
Contraindications
Danazol is
contraindication during
pregnancy because it has the potential to
virilization female
. Women taking danazol should practice effective
contraception to prevent pregnancy if sexually active.
Since danazol is metabolism 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.
Side effects
Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (
hirsutism),
acne vulgaris, irreversible
voice change,
or adverse
lipid profile.
In addition,
breast atrophy and decreased breast size may occur.
The drug may also cause
, elevation of liver enzymes, and
mood disorder.
The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer.
Pharmacology
Pharmacodynamics
Danazol possesses a complex
pharmacology, with multiple mechanisms of action.
These include direct binding to and activation of sex hormone receptors, direct
enzyme inhibitor of
involved in
steroidogenesis, and direct binding to and occupation of
steroid hormone and consequent displacement of steroid hormones from these proteins.
The drug is characterized as a weak
androgen and
anabolic steroid, a weak progestogen, a weak
antigonadotropin, a weak steroidogenesis inhibitor, and a functional
antiestrogen.
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).
As an androgen, danazol is described as weak, being about 200-fold less potent than testosterone in
.
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).
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.
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.
Danazol is considered to act significantly as an agonist of the GR, and, thus, as a
glucocorticoid.
In accordance, it can suppress the immune system at sufficient dosages.
| Relative affinities (%) of danazol and metabolites |
|
| 10 |
| 0.33 |
| ? |
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the , testosterone (c = androstanolone) for the , hydrocortisone for the (b = dexamethasone), aldosterone for the , androstanolone for , and cortisol for . a = 1-hour incubation time (4 hours is standard for this assay; may affect affinity value). Sources: |
| Absolute affinities (nM) of danazol |
|
| Agonist |
| Agonist–antagonist |
| Agonist |
| Agonist |
Sources: |
Inhibition of steroidogenesis enzymes
Danazol has been found to act as an
enzyme 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.
It has also been found to be a weak inhibitor of steroid sulfatase (K
i = 2.3–8.2 μM), the enzyme that converts into and
estrone sulfate into
estrone (which can then respectively be transformed into estrone (with
androstenedione as an intermediate) and
estradiol),
though another study reported its inhibition to be potent and potentially clinically relevant.
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.
In accordance with its steroidogenesis inhibition, clinical studies have demonstrated that danazol directly and markedly inhibits adrenal gland, ovary, and testicle steroidogenesis in vivo.
| Danazol at steroiodgenic enzymes |
|
| ? |
| 4.3% |
| 2.9% |
| 3.9% |
| 15% |
| 37% |
| 21% |
| 0% |
Sources: |
For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.
Occupation and downregulation of carrier proteins
| Protein binding of testosterone in women |
|
| 60% |
| 18% |
Sources: |
Danazol is known to bind to two steroid hormone carrier proteins: sex hormone-binding globulin (SHBG), which binds and ; and corticosteroid-binding globulin (CBG), which binds progesterone and cortisol.
As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.
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.
Antigonadotropic activity
Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the
pituitary gland, danazol produces
antigonadotropic effects.
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),
the drug prevents the mid-cycle surge in the levels of these hormones during the
menstrual cycle.
By doing this, it suppresses increases in estrogen and progesterone levels at this time and prevents
ovulation.
Mechanism of action in endometriosis
Because danazol reduces estrogen production and levels,
it has functional
properties.
The combination of its antiestrogenic, androgenic, and progestogenic or
actions cause
atrophy of the
endometrium, which alleviates the symptoms of endometriosis.
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.
However, even at the highest dosage assessed (800 mg/day),
spermatogenesis remained unaffected.
Pharmacokinetics
The
bioavailability of danazol is low.
In addition, circulating levels of danazol do not increase proportionally with increasing doses, indicating that there is a saturation of bioavailability.
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.
Similar findings were observed for chronic administration.
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.
Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.
Steady-state levels of danazol are achieved after 6 days of twice-daily administration.
Danazol is
lipophilic and can partition into
, which indicates that it is likely to distribute deeply into tissue compartments.
The volume of distribution of danazol is 3.4 L.
Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.
Danazol is metabolism in the liver by such as CYP3A4.
Chemistry
Danazol, also known as 2,3-isoxazol-17α-ethynyltestosterone or as 17α-ethynyl-17β-hydroxyandrost-4-en-2,3-disoxazole, is a synthetic
androstane steroid and a derivative of testosterone and
ethisterone (17α-ethynyltestosterone).
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).
Ethisterone is a weak
progestin with weak androgenic activity.
History
Danazol was synthesized in 1963 by a team of scientists at
Sterling Drug in Rensselaer, New York by a team that included Helmutt Neumann, Gordon Potts, W.T. Ryan, and Frederik W. Stonner.
[ pp. 126, note 158, 130, notes 1513, 2369, citing ] It was approved by the Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.
Society and culture
Generic names
Danazol is the
generic term of the drug and its , , , , , , and .
It is also known by its developmental code name
WIN-17757.
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 drug), Dorink, Dzol, Ectopal, Elle, Gonablok, Gong Fu Yi Kang, Gynadom, Kodazol, Kupdina, Ladogal, Lozana, Mastodanatrol, Nazol, Norciden, Vabon, and Winobanin.
Availability
Danazol is available in the
United States,
Europe, and widely elsewhere throughout the world.
Research
Danazol has been studied in the treatment of
breast cancer in women, but produced relatively low response rates of about 15 to 20%.
Low-dose danazol has been investigated in the treatment of diabetic macular edema in a phase III clinical trial.
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. Hematology 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.
Further reading
