معني كلمة danazol

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معني كلمة danazol
معني كلمة danazol

Danazol, sold under the brand name Danocrine among others, is a medication which is used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions.[1][3][9][10][11] It is taken by mouth.[3]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening.[3][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.[6][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Due to their improved side-effect profiles, particularly their lack of masculinizing side effects, danazol has largely been replaced by gonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis.[5]

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]

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[3] 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.[3]معني كلمة danazol

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]

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[5] or adverse blood lipid profiles.[22] In addition, breast atrophy and decreased breast size may occur.[5] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[22] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

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]

Danazol possesses a complex pharmacology, with multiple mechanisms of action.[6][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.[5][6][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]

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).[5][6] 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).[6] 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.[6] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid.[6] In accordance, it can suppress the immune system at sufficient dosages.[6][13][15]

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/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase.[6] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-S into DHEA 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.[6] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[6]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[6]

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.[5][6] Binding of danazol to SHBG is considered to be more important clinically.[6] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol.[5][6] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[6]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[6][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.[6][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.[5][6] 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]

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[6] 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.[5][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]

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.[5][6][15][37][41]

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]

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.[3] 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.[3] Similar findings were observed for chronic administration.[3] 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.[3] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[3]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[3] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[3] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.[4][5][6]

Danazol is metabolized in the liver by enzymes such as CYP3A4.[1][2] 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.[1][3] 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),[2][3][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.[3] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[3]

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).[2][13] Ethisterone is a weak progestin with weak androgenic activity.[45]

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. Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[13][18]

Danazol is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN.[1][9][10][11][46] It is also known by its developmental code name WIN-17757.[1][9][10][11][46]

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.[1][9][10][11][46]

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[1][10][46]

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]

Danazol, sold under the brand name Danocrine among others, is a medication which is used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions.[1][3][9][10][11] It is taken by mouth.[3]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening.[3][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.[6][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.[5]

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]

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[3] 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.[3]معني كلمة danazol

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]

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[5] or adverse blood lipid profiles.[22] In addition, breast atrophy and decreased breast size may occur.[5] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[22] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

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]

Danazol possesses a complex pharmacology, with multiple mechanisms of action.[6][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.[5][6][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]

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).[5][6] 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).[6] 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.[6] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid.[6] In accordance, it can suppress the immune system at sufficient dosages.[6][13][15]

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/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase.[6] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-S into DHEA 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.[6] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[6]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[6]

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.[5][6] Binding of danazol to SHBG is considered to be more important clinically.[6] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol.[5][6] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[6]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[6][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.[6][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.[5][6] 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]

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[6] 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.[5][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]

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.[5][6][15][37][41]

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]

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.[3] 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.[3] Similar findings were observed for chronic administration.[3] 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.[3] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[3]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[3] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[3] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.[4][5][6]

Danazol is metabolized in the liver by enzymes such as CYP3A4.[1][2] 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.[1][3] 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),[2][3][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.[3] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[3]

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).[2][13] Ethisterone is a weak progestin with weak androgenic activity.[45]

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. Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[13][18]

Danazol is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN.[1][9][10][11][46] It is also known by its developmental code name WIN-17757.[1][9][10][11][46]

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.[1][9][10][11][46]

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[1][10][46]

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]

Danazol, sold under the brand name Danocrine among others, is a medication which is used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions.[1][3][9][10][11] It is taken by mouth.[3]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening.[3][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.[6][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.[5]

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]

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[3] 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.[3]معني كلمة danazol

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]

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[5] or adverse blood lipid profiles.[22] In addition, breast atrophy and decreased breast size may occur.[5] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[22] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

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]

Danazol possesses a complex pharmacology, with multiple mechanisms of action.[6][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.[5][6][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]

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).[5][6] 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).[6] 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.[6] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid.[6] In accordance, it can suppress the immune system at sufficient dosages.[6][13][15]

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/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase.[6] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-S into DHEA 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.[6] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[6]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[6]

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.[5][6] Binding of danazol to SHBG is considered to be more important clinically.[6] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol.[5][6] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[6]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[6][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.[6][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.[5][6] 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]

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[6] 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.[5][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]

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.[5][6][15][37][41]

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]

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.[3] 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.[3] Similar findings were observed for chronic administration.[3] 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.[3] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[3]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[3] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[3] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.[4][5][6]

Danazol is metabolized in the liver by enzymes such as CYP3A4.[1][2] 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.[1][3] 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),[2][3][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.[3] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[3]

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).[2][13] Ethisterone is a weak progestin with weak androgenic activity.[45]

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. Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[13][18]

Danazol is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN.[1][9][10][11][46] It is also known by its developmental code name WIN-17757.[1][9][10][11][46]

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.[1][9][10][11][46]

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[1][10][46]

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]

Danazol, sold under the brand name Danocrine among others, is a medication which is used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions.[1][3][9][10][11] It is taken by mouth.[3]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening.[3][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.[6][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.[5]

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]

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[3] 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.[3]معني كلمة danazol

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]

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[5] or adverse blood lipid profiles.[22] In addition, breast atrophy and decreased breast size may occur.[5] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[22] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

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]

Danazol possesses a complex pharmacology, with multiple mechanisms of action.[6][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.[5][6][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]

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).[5][6] 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).[6] 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.[6] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid.[6] In accordance, it can suppress the immune system at sufficient dosages.[6][13][15]

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/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase.[6] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-S into DHEA 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.[6] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[6]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[6]

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.[5][6] Binding of danazol to SHBG is considered to be more important clinically.[6] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol.[5][6] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[6]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[6][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.[6][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.[5][6] 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]

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[6] 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.[5][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]

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.[5][6][15][37][41]

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]

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.[3] 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.[3] Similar findings were observed for chronic administration.[3] 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.[3] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[3]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[3] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[3] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.[4][5][6]

Danazol is metabolized in the liver by enzymes such as CYP3A4.[1][2] 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.[1][3] 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),[2][3][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.[3] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[3]

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).[2][13] Ethisterone is a weak progestin with weak androgenic activity.[45]

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. Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[13][18]

Danazol is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN.[1][9][10][11][46] It is also known by its developmental code name WIN-17757.[1][9][10][11][46]

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.[1][9][10][11][46]

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[1][10][46]

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]

Danazol, sold under the brand name Danocrine among others, is a medication which is used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema, and other conditions.[1][3][9][10][11] It is taken by mouth.[3]

The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening.[3][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.[6][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.[5]

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]

Danazol comes in the form of 50, 100, and 200 mg oral capsules.[3] 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.[3]معني كلمة danazol

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]

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[5] or adverse blood lipid profiles.[22] In addition, breast atrophy and decreased breast size may occur.[5] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[22] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

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]

Danazol possesses a complex pharmacology, with multiple mechanisms of action.[6][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.[5][6][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]

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).[5][6] 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).[6] 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.[6] Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid.[6] In accordance, it can suppress the immune system at sufficient dosages.[6][13][15]

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/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase.[6] It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts DHEA-S into DHEA 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.[6] The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.[6]

For reference, circulating concentrations of danazol are in the range of 2 μM at a dosage of 600 mg/day in women.[6]

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.[5][6] Binding of danazol to SHBG is considered to be more important clinically.[6] By occupying SHBG and CBG, danazol increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol.[5][6] The table to the right shows the difference in testosterone levels in premenopausal women treated with danazol.[6]

As can be seen, the percentage of free testosterone is tripled in women being treated with danazol.[6][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.[6][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.[5][6] 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]

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[6] 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.[5][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]

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.[5][6][15][37][41]

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]

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.[3] 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.[3] Similar findings were observed for chronic administration.[3] 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.[3] Following administration of danazol, peak concentrations occur after 2 to 8 hours, with a median of 4 hours.[3]Steady-state levels of danazol are achieved after 6 days of twice-daily administration.[3] Danazol is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments.[3] The volume of distribution of danazol is 3.4 L.[7] Danazol is known to be plasma protein bound to albumin, SHBG, and CBG.[4][5][6]

Danazol is metabolized in the liver by enzymes such as CYP3A4.[1][2] 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.[1][3] 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),[2][3][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.[3] Danazol is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.[3]

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).[2][13] Ethisterone is a weak progestin with weak androgenic activity.[45]

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. Food and Drug Administration in 1971 as the first drug in the country to specifically treat endometriosis.[13][18]

Danazol is the generic name of the drug and its INN, USAN, USP, BAN, DCF, DCIT, and JAN.[1][9][10][11][46] It is also known by its developmental code name WIN-17757.[1][9][10][11][46]

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.[1][9][10][11][46]

Danazol is available in the United States, Europe, and widely elsewhere throughout the world.[1][10][46]

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]

The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites in breast milk.

Every drug has specific information listed in its product literature. The British National Formulary used to provide a table of drugs to be avoided or used with caution in pregnancy, and did so using a limited number of key phrases, but now Appendix 4 (which was the Pregnancy table) has been removed. Appendix 4 is now titled “Intravenous Additives”.[1] However, information that was previously available in the former Appendix 4 (pregnancy) and Appendix 5 (breast feeding) is now available in the individual drug monographs.[2]

American law requires that certain drugs and biological products must be labelled very specifically. Title 21, Part 201.57 (9)(i) of the Code of Federal Regulations lists specific requirements regarding the labeling of drugs with respect to their effects on pregnant populations, including a definition of a “pregnancy category”. These rules are enforced by the Food and Drug Administration.

To supplement this information, FDA publishes additional rules regarding pregnancy and lactation labeling.[3]

The FDA does not regulate labeling for all hazardous and non-hazardous substances. Many substances, including alcohol, are widely known to cause serious hazards to pregnant women and their fetus, including fetal alcohol syndrome. Many other pollutants and hazardous materials are similarly known to cause reproductive harm. However, some of these substances are not subject to drug labeling laws, and are therefore not assigned a “Pregnancy Category” per 21 CFR 201.57.
معني كلمة danazol

One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA.

On December 13, 2014, the FDA published the Pregnancy and Lactation Labeling Final Rule (PLLR), which changed the labeling requirements for the pregnancy and lactation sections for prescription drugs and biological agents.[3] The final rule removed the pregnancy letter categories, and created descriptive subsections for pregnancy exposure and risk, lactation, and effects to reproductive potential for females and males. Labeling changes from this rule began on June 30, 2015, with all submissions for prescription drugs and biological agents using the labeling changes immediately. Previously approved drugs from June 30, 2001 will switch to the new labeling gradually. The rule does not affect the labeling of over-the-counter drugs.

Australia has a slightly different pregnancy category system[4] from the United States – notably the subdivision of Category B. (For drugs in B1, B2 and B3 categories, human data are lacking or inadequate. Subcategorisation is based on animal data, and allocation of a B category does not imply greater safety than C category).[5] The system, as outlined below, was developed by medical and scientific experts based on available evidence of risks associated with taking particular medicines while pregnant. Being general in nature it is not presented as medical advice to health professionals or the public.

Some prescribing guides, such as the Australian Medicines Handbook, are shifting away from using pregnancy categories since, inherent in these categories, there is an implied assumption that the alphabetical code is one of safety when this is not always the case. Categorisation does not indicate which stages of fetal development might be affected and does not convey information about the balance between risks and benefits in a particular situation. Additionally, categories are not necessarily maintained or updated with availability of new data.[6]

The data presented is for comparative and illustrative purposes only, and may have been superseded by updated data.

The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites in breast milk.

Every drug has specific information listed in its product literature. The British National Formulary used to provide a table of drugs to be avoided or used with caution in pregnancy, and did so using a limited number of key phrases, but now Appendix 4 (which was the Pregnancy table) has been removed. Appendix 4 is now titled “Intravenous Additives”.[1] However, information that was previously available in the former Appendix 4 (pregnancy) and Appendix 5 (breast feeding) is now available in the individual drug monographs.[2]

American law requires that certain drugs and biological products must be labelled very specifically. Title 21, Part 201.57 (9)(i) of the Code of Federal Regulations lists specific requirements regarding the labeling of drugs with respect to their effects on pregnant populations, including a definition of a “pregnancy category”. These rules are enforced by the Food and Drug Administration.

To supplement this information, FDA publishes additional rules regarding pregnancy and lactation labeling.[3]

The FDA does not regulate labeling for all hazardous and non-hazardous substances. Many substances, including alcohol, are widely known to cause serious hazards to pregnant women and their fetus, including fetal alcohol syndrome. Many other pollutants and hazardous materials are similarly known to cause reproductive harm. However, some of these substances are not subject to drug labeling laws, and are therefore not assigned a “Pregnancy Category” per 21 CFR 201.57.
معني كلمة danazol

One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA.

On December 13, 2014, the FDA published the Pregnancy and Lactation Labeling Final Rule (PLLR), which changed the labeling requirements for the pregnancy and lactation sections for prescription drugs and biological agents.[3] The final rule removed the pregnancy letter categories, and created descriptive subsections for pregnancy exposure and risk, lactation, and effects to reproductive potential for females and males. Labeling changes from this rule began on June 30, 2015, with all submissions for prescription drugs and biological agents using the labeling changes immediately. Previously approved drugs from June 30, 2001 will switch to the new labeling gradually. The rule does not affect the labeling of over-the-counter drugs.

Australia has a slightly different pregnancy category system[4] from the United States – notably the subdivision of Category B. (For drugs in B1, B2 and B3 categories, human data are lacking or inadequate. Subcategorisation is based on animal data, and allocation of a B category does not imply greater safety than C category).[5] The system, as outlined below, was developed by medical and scientific experts based on available evidence of risks associated with taking particular medicines while pregnant. Being general in nature it is not presented as medical advice to health professionals or the public.

Some prescribing guides, such as the Australian Medicines Handbook, are shifting away from using pregnancy categories since, inherent in these categories, there is an implied assumption that the alphabetical code is one of safety when this is not always the case. Categorisation does not indicate which stages of fetal development might be affected and does not convey information about the balance between risks and benefits in a particular situation. Additionally, categories are not necessarily maintained or updated with availability of new data.[6]

The data presented is for comparative and illustrative purposes only, and may have been superseded by updated data.

1LHW, 1D2S, 1F5F, 1KDK, 1KDM, 1LHN, 1LHO, 1LHU, 1LHV

6462

20415

ENSG00000129214

ENSMUSG00000005202

معني كلمة danazol

P04278

P97497

NM_001289114NM_001289115NM_001289116

NM_011367

NP_001276043NP_001276044NP_001276045

NP_035497

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds.[5]

Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to serum albumin (~54%), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1 to 2% is unbound, or “free,” and thus biologically active and able to enter a cell and activate its receptor. SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG. The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone > androstenediol > estradiol > estrone.[6] DHT binds to SHBG with about 5 times the affinity of testosterone and about 20 times the affinity of estradiol.[7]Dehydroepiandrosterone (DHEA) is weakly bound to SHBG, but dehydroepiandrosterone sulfate is not bound to SHBG.[6]Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.[8]Estrone sulfate and estriol are also poorly bound by SHBG.[9] Less than 1% of progesterone is bound to SHBG.[10]

SHBG levels are usually about twice as high in women than in men.[7] In women, SHBG serves to limit exposure to both androgens and estrogens.[7] Low SHBG levels in women have been associated with hyperandrogenism and endometrial cancer due to heightened exposure to androgens and estrogens, respectively.[7] During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by 5- to 10-fold.[7] The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta.[7] A case report of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.[7]

SHBG is produced mostly by the liver and is released into the bloodstream. Other sites that produce SHBG include the brain, uterus, testes, and placenta.[11] Testes-produced SHBG is called androgen-binding protein.

The gene for SHBG is called Shbg located on chromosome 17[11] on the short arm between the bands 17p12→p13.[12] Overlapping on the complementary DNA strand is the gene for spermidine/spermine N1-acetyltransferase family member 2 (SAT2). Nearby are the genes for p53 and ATP1B2, and fragile X mental retardation, autosomal homolog 2 (FXR2) on the complementary strand.[13] There are eight exons, of which exon 1 has three variations called 1L, 1T and 1N which are triggered by three promoters: PL, PT and PN respectively. SHBG comes with the 1L, 2, 3, 4, 5, 6, 7, and 8 exons connected together. A variation includes SHBG-T which is missing exon 7 but with exon 1T promoted by promoter PT on the opposite strand, which shared with that for SAT2.[14]

There are variations in the genetic material for this protein that have different effects.
In humans common polymorphisms include the following:

Rs6259, also called Asp327Asn location 7633209 on Chromosome 17, results in there being an extra N-glycosilation site, and so an extra sugar can be attached. This results in a longer circulation half-life for the protein, and raised levels. A health effect is a lowered risk of endometrial cancer, and another is an increased risk of systemic lupus erythematosus.[15]

Rs6258 also called Ser156Pro is at position 7631360 on the Chromosome 17.

Rs727428 position 7634474 is in several percent of humans.[16]

(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.[17]

The mechanism of activating the promoter for SHBG in the liver involves hepatocyte nuclear factor 4 alpha (HNF4A) binding to a DR1 like cis element which then stimulate production. Competing with HNF4A at a third site on the promoter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then COUP-TF binds to the first site and turns off production of SHBG.[5]

Sex hormone-binding globulin is homodimeric, meaning it has two identical peptide chains making up its structure. The amino acid sequence is the same as for androgen-binding protein but that has different oligosaccharides attached and is produced in testes.[11]

SHBG has two two laminin G-like domains which form pockets that bind hydrophobic molecules. The steroids are bound by the LG domain at the amino end of the protein.[5] Inside the pocket of the domain is a serine residue that attracts the two different types of steroids at different points, thus changing their orientation. Androgens bind at the C3 functional groups on the A ring, and estrogens bind via a hydroxyl attached to C17 on the D ring. The two different orientations change a loop over the entrance to the pocket and the position of trp84 (in humans). Thus the whole protein signals what hormone it carries on its own surface.[5] The steroid binding LG domain is coded by exons 2 to 5.[5] A linker region joins the two LG domains together.[5]

When first produced the SHBG precursor has a leading signal peptide attached with 29 amino acids. The remaining peptide has 373 amino acids.[18] There are two sulfur bridges.

The sugars are attached at two different N-glycosylation points on apsparagine (351 and 367) and one O-glycosylation (7) point on threonine.[18]

A calcium ion is needed to link the two elements of the dimer together. Also a zinc ion is used to orient an otherwise disorganised part of the peptide chain.[5]

SHBG has both enhancing and inhibiting hormonal influences. It decreases with high levels of insulin, growth hormone, insulin-like growth factor 1 (IGF-1), androgens, prolactin and transcortin. High estrogen and thyroxine levels cause it to increase.

In an effort to explain obesity-related reductions in SHBG, recent evidence suggests sugar or monosaccharide-induced hepatic lipogenesis, hepatic lipids in general, and cytokines like TNF-alpha and Interleukin reduce SHBG, whereas insulin does not. As an example anti-psoriatic drugs that inhibit TNF-alpha cause an increase in SHBG. The common downstream mechanism for all of these, including the effect of thyroid hormones[19] was downregulation of HNF4, hepatocyte nuclear factor 4.[20][21][22][23]

Reference ranges for blood tests for SHBG have been developed:[24]

SHBG levels are decreased by androgens, administration of anabolic steroids,[25]polycystic ovary syndrome, hypothyroidism, obesity, Cushing’s syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[26] SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction of more than 50 percent increases SHBG, while lowering free and total testosterone and estradiol. DHEA-S, which lacks affinity for SHBG, is not affected by calorie restriction.[27]Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[28]

In the womb the human fetus has a low level of SHBG allowing increased activity of sex hormones. After birth, the SHBG level rises and remains at a high level throughout childhood. At puberty the SHBG level halves in girls and goes down to a quarter in boys.[5] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In pregnant women in the last two thirds of pregnancy the SHBG level escalates to five to ten times the usual level for a woman. A hypothesis is that this protects against the effect of hormone produced by the fetus.[5]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[5] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[5]

Reduced levels of SHBG and also certain polymorphisms of the SHBG gene are implicated in the development of insulin resistance and type 2 diabetes.[29] Such effects apparently involve direct action at the cellular level where it became apparent that cell membranes of certain tissues contain specific high-affinity SHBG receptors.[30]

Oral contraceptives containing ethinylestradiol can increase SHBG levels by 2- to 4-fold and decrease free testosterone concentrations by 40 to 80% in women.[31] They can be used to treat symptoms of hyperandrogenism like acne and hirsutism.[31][7] Some oral contraceptives, namely those containing high doses of ethinylestradiol (which have been discontinued and are no longer marketed), can increase SHBG levels by as much as 5- to 10-fold.[7]

Some medications, such as certain anabolic steroids like mesterolone and danazol and certain progestins like levonorgestrel and norethisterone, have high affinity for SHBG and can bind to it and displace endogenous steroids from it, thereby increasing free concentrations of these endogenous steroids.[32][33][34] It has been estimated that therapeutic levels of danazol, methyltestosterone, fluoxymesterone, levonorgestrel, and norethisterone would respectively occupy or displace from testosterone 83–97%, 48–69%, 42–64%, 16–47%, and 4–39% of SHBG binding sites, while others with low affinity for SHBG such as ethinylestradiol, cyproterone acetate, and medroxyprogesterone acetate would occupy or displace from testosterone 1% or fewer SHBG binding sites.[32][35]

When checking serum estradiol or testosterone, a total level that includes free and bound fractions can be assayed, or the free portion may be measured alone. A free androgen index expresses the ratio of testosterone to SHBG and can be used to summarize the activity of free testosterone. The best test for testosterone is the bioavailable testosterone. Sex hormone-binding globulin can be measured separately from the total fraction of testosterone.

SHBG has been known under a variety of different names including:[41][42][43]

1d2s: CRYSTAL STRUCTURE OF THE N-TERMINAL LAMININ G-LIKE DOMAIN OF SHBG IN COMPLEX WITH DIHYDROTESTOSTERONE

1f5f: CRYSTAL STRUCTURE OF THE N-TERMINAL G-DOMAIN OF SHBG IN COMPLEX WITH ZINC

معني كلمة danazol

1kdk: THE STRUCTURE OF THE N-TERMINAL LG DOMAIN OF SHBG IN CRYSTALS SOAKED WITH EDTA

1kdm: THE CRYSTAL STRUCTURE OF THE HUMAN SEX HORMONE-BINDING GLOBULIN (TETRAGONAL CRYSTAL FORM)

1lhn: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 5ALPHA-ANDROSTANE-3BETA,17ALPHA-DIOL

1lho: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 5ALPHA-ANDROSTANE-3BETA,17BETA-DIOL

1lhu: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH ESTRADIOL

1lhv: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH NORGESTREL

1lhw: CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 2-METHOXYESTRADIOL

2VDX, 2VDY, 4BB2, 4C41, 4C49

866

12401

ENSG00000277405ENSG00000170099

ENSMUSG00000060807

معني كلمة danazol

P08185

Q06770

NM_001756

NM_007618

NP_001747

NP_031644

Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein that in humans is encoded by the SERPINA6 gene. It is an alpha-globulin.[5][6][7]

This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucocorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors (serpins) which have evolved by duplication events.[7]

Transcortin binds several steroid hormones at high rates:

In addition, approximately 4% of serum testosterone is bound to transcortin.[11] A similarly small fraction of serum estradiol is bound to transcortin as well.[citation needed]

Transcortin is produced by the liver and is increased by estrogens.[12]

Mutations in this gene are rare. Only four mutations have been described, often in association with fatigue and chronic pain.[13] This mechanism for these symptoms is not known. This condition must be distinguished from secondary hypocortisolism. Exogenous hydrocortisone does not appear to improve the fatigue.

Hepatic synthesis of corticosteroid-binding globulin more than doubles in pregnancy; that is, bound plasma cortisol in term pregnancy is approximately 2.5 times that of nonpregnant women.[14]


دانازول (Danazol) هو هورمون اصطناعي يُثَبِّط إفراز الهورمونات الجنسية من الغدة النُّخامية (Pituitary Gland). استعماله الأساسي هو في العلاج المطوّل للانتباذ البِطاني الرَّحِمي (Endometriosis)، وهو مرض تنمو به أجزاء من نسيج بِطانة الرحم خارج الرحم. يستعمل الدانازول أيضًا لتخفيف الألم، الحساسية والتكتل في الثدْيَيْن الناجمة عن مرض كيسي ليفي (Fibrocystic). يستعمل الدانازول أحيانًا لعلاج الحَيْض مع نزيف حاد ولتقليل الانتفاخ في ثديَيْ الرجال.

يمكن أيضًا إعطاء الدانازول (Danazol) للأشخاص المعرّضين للإصابة بالوَذَمَة الأُرْجِيَّة الوراثية (مرض نادر يؤدي لانتفاخ المزمار).

يُخِلُّ العلاج بالدانازول في العديد من الأحيان بانتظام الحيض. توقف الحيض هو ظاهرة طبيعية وقت علاج الانتباذ البطاني الرحمي. تشمل التأثيرات الجانبية الأخرى: غثيانًا، دوخة، طفحًا جلديًّا، ألم ظهر، زيادة بالوزن وموجات حرارة. قد تصاب النساء اللاتي يتعاطَيْن جرعات كبيرة من  الدانازول بنمو شعر مكثّف وبتثخين (خشونة) الصوت.


أقراص


2 – 4 مرات في اليوم مع الطعام.

معني كلمة danazol

الكبار: انتباذ بطاني رحمي: 200 – 800 ملغم لليوم حسب حدة المرض.

تتم ملاحظة التأثيرات الجانبية والتأثيرات الإيجابية في المرض الكيسي الليفي خلال شهر واحد. في الانتباذ البِطاني الرَّحِمي قد يمر 3 – 12 شهرًا قبل الإحساس بالتأثيرات الإيجابية.

يحفظ بعبوة محكمة الإغلاق في مكان بارد وجاف، بعيدًا عن متناول أيدي الأطفال.

يجب الأخذ بشكل فوري عند التذكر. إذا كانت هناك حاجة لأخذ الجرعة التالية خلال 4 ساعات، خذ جرعة واحدة الآن ولا تأخذ الجرعة التالية.

لا يجوز إيقاف الدواء دون استشارة الطبيب، من الممكن عودة الأعراض.

لا داعي للقلق من أخذ جرعة زائدة بشكل عَرَضي. ولكن في حال ملاحظة أعراض خاصة، أو إذا أخذت جرعة زائدة أكبر، يجب إخبار الطبيب.


يمنع استعماله بأي شكل من الأشكال (X).

المعلومات الواردة عن الدواء مبنية على النشرات الطبية للدواء، مع هذا فإنها لا تشكل بديلا عن استشارة الطبيب.

المواد المنشورة في موقع ويب طب هي بمثابة معلومات فقط ولا يجوز اعتبارها استشارة طبية أو توصية علاجية. يجب استشارة الطبيب في حال لم تختفي الأعراض. – اقرأ المزيد

حقوق الطبع محفوظة – ويب طب م.ض 2017-2011

أخطاء شائعة


Most people loved The Matrix, but I didn’t _________ it that much.

ابدأ اللّعبة الآن

التكية – موسوعة عربية شاملة

دواء دانازول “Danazol” كبسول يُستخدم لعلاج بعض الأمراض التي يُعاني منها كثير من الأشخاص مثل مرض الثدي الكيسي الليفي الذي هو عبارة عن تكيس الثدي والذي يكون من الضروري العلاج منه سريعاً فإنه دواء يحتوي على مجموع من الفوائد والعناصر المفيدة التي تعود على الصحة بالإيجاب واليوم سوف نتعرف عبر مقالنا على التفاصيل التي تخص هذا الدواء من جرعات واستخدامات.

محتويات

دواء دانازول من الأدوية التي تكون سريعة المفعول والتي تكون ذات نتيجة سريعة وإيجابية في حيث انه غني بكثير من العناصر المفيدة التي تكون ذات مواد طبية قادرة على التخلص من الأمراض في أسرع وقت ممكن.معني كلمة danazol

يُعتبر هذا الدواء من أكثر الأدوية التي يوجد بها آثار جانبية لذلك يكون من الضروري تجنب أي منها حتى لا تكون سبباً في الكثير من المشاكل الصحية للمريض واليوم سوف نوضح عبر مقالنا الآثار هذه لتجنبها.

أ فيرين بلس – A ferin Plus

هستوب – Histop

أ سنوترين – A CNOTREN

أي زد فيتال – A Z VITAL

لن يتم نشر عنوان بريدك الإلكتروني.

جديد دليل الأدوية

بي كور – B Cor

جريبوستاد – Grippostad

سيفوتيل – Cefutil

ريجيكول – Regicol

ديـكساتوبرين – DEXATOBRIN

رينوتوس – Rhinotus

تريفلوكان – TREFLUCAN

ديباكين – DEPAKINE

أورنيداز – ORNIDAZ

اوكسيتروبيل – Oxitropil

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What is the most important information i should know about danazol danocrine .

Abnormalities in laboratory tests may occur during therapy with Danazol including CPKglucose toleranceglucagonthyroid binding globulinsex hormone binding globulinother plasma proteinslipids and lipoproteins.معني كلمة danazol

Danazol has been used to treat women with endometriosis since the 1970s1It was the most commonly used drug in the early 1980sbut its use declined markedly after the introduction of the GnRH agonists in the late 1980s and early 1990s.

You may need to have a negative pregnancy test before starting this treatment.

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it is recommended that patients receiving danazol be monitored for hepatic dysfunction by laboratory tests and clinical observation.

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