Product Information
Registration Status: ActiveQLAIRA FILM-COATED TABLET is approved to be sold in Singapore with effective from 2010-08-13. It is marketed by BAYER (SOUTH EAST ASIA) PTE LTD, with the registration number of SIN13847P.
This product contains Estradiol 1mg,Estradiol 1mg,Dienogest 3mg,Estradiol 1mg,Dienogest 3mg,Estradiol 1mg, in the form of TABLET, FILM-COATED. It is approved for ORAL use.
This product is manufactured by BAYER WEIMAR GMBH UND CO. KG (WEIMAR PLANT) in GERMANY.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
Estradiol (also known as E2 or 17β-estradiol) is a naturally occurring hormone that circulates endogenously within the human body. It is the most potent form of mammalian estrogenic steroids and acts as the major female sex hormone. As such, estradiol plays an essential role in the regulation of the menstrual cycle, in the development of puberty and secondary female sex characteristics, as well as in ageing and several hormonally-mediated disease states. Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. Estradiol is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen production such as menopausal and peri-menopausal symptoms as well as hypoestrogenism. It is also used in transgender hormone therapy, as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol), and is sometimes used for the palliative treatment of some hormone-sensitive cancers like breast and prostate cancer. Estradiol is available in a number of formulations including oral, transdermal, and injectable. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women [FDA Label]. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). It is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter the systemic circulation and exert its estrogenic effects [A12102]. Esterification of estradiol aims to improve absorption after oral administration (such as with Estradiol valerate) or to sustain release from intramuscular depot injections (such as with Estradiol Cypionate) through improved lipophilicity [T84]. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as a number of concerns were raised regarding the use of estrogen [A31626]. Specifically, the combined estrogen–progestin arm was discontinued after approximately five years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events [A31627]. Following extensive critique of the WHI results in the years following its release, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years post-menopause) in low doses, and in women without a history of breast cancer or at increased risk of cardiovascular or thromboembolic disease [A31628]. Notably, use of estrogen for menopausal symptoms should always be accompanied by a progestin component due to estrogen's effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer in the long-term. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination Oral Contraceptive Pills (OCPs). Ethinyl Estradiol differs from Estradiol in that it has improved biovailability and greater resistance to metabolism, making it more suitable for oral administration.
Indication
Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of post-menopausal osteoarthritis. It is also used for the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Mechanism of Action
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
Pharmacokinetics
- Absorption
- 43%
- Distribution
- Metabolism
- Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.
- Elimination
Active Ingredient/Synonyms
(17β)-estra-1,3,5(10)-triene-3,17-diol | 17beta oestradiol | 17β-estra-1,3,5(10)-triene-3,17-diol | 17β-estradiol | 17β-oestradiol | beta-Estradiol | cis-Estradiol | Estradiol | Estradiol-17beta | Estradiolum | Estradiol |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Estradiol (also known as E2 or 17β-estradiol) is a naturally occurring hormone that circulates endogenously within the human body. It is the most potent form of mammalian estrogenic steroids and acts as the major female sex hormone. As such, estradiol plays an essential role in the regulation of the menstrual cycle, in the development of puberty and secondary female sex characteristics, as well as in ageing and several hormonally-mediated disease states. Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. Estradiol is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen production such as menopausal and peri-menopausal symptoms as well as hypoestrogenism. It is also used in transgender hormone therapy, as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol), and is sometimes used for the palliative treatment of some hormone-sensitive cancers like breast and prostate cancer. Estradiol is available in a number of formulations including oral, transdermal, and injectable. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women [FDA Label]. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). It is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter the systemic circulation and exert its estrogenic effects [A12102]. Esterification of estradiol aims to improve absorption after oral administration (such as with Estradiol valerate) or to sustain release from intramuscular depot injections (such as with Estradiol Cypionate) through improved lipophilicity [T84]. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as a number of concerns were raised regarding the use of estrogen [A31626]. Specifically, the combined estrogen–progestin arm was discontinued after approximately five years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events [A31627]. Following extensive critique of the WHI results in the years following its release, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years post-menopause) in low doses, and in women without a history of breast cancer or at increased risk of cardiovascular or thromboembolic disease [A31628]. Notably, use of estrogen for menopausal symptoms should always be accompanied by a progestin component due to estrogen's effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer in the long-term. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination Oral Contraceptive Pills (OCPs). Ethinyl Estradiol differs from Estradiol in that it has improved biovailability and greater resistance to metabolism, making it more suitable for oral administration.
Indication
Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of post-menopausal osteoarthritis. It is also used for the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Mechanism of Action
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
Pharmacokinetics
- Absorption
- 43%
- Distribution
- Metabolism
- Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.
- Elimination
Active Ingredient/Synonyms
(17β)-estra-1,3,5(10)-triene-3,17-diol | 17beta oestradiol | 17β-estra-1,3,5(10)-triene-3,17-diol | 17β-estradiol | 17β-oestradiol | beta-Estradiol | cis-Estradiol | Estradiol | Estradiol-17beta | Estradiolum | Estradiol |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Dienogest is an orally-active semisynthetic progestogen which also possesses the properties of 17α-hydroxyprogesterone. It is a derivative of 19-nortestosterone and has antiandrogenic properties. It is primarily used as a contraceptive in combination with ethinylestradiol, or in other combination form pills approved in United States and Europe however it is not available in the US by itself. In Europe, Australia, Malaysia, Singapore and Japan, dienogest single therapy is an approved treatment for endometriosis to alleviate painful symptoms of endometriosis and reduce endometriotic lesions [A20330]. Dienogest is commonly marketed as Visanne, Natazia and Qlaira.
Indication
Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol.
Mechanism of Action
Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use [A20331]. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium [L932]. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue [L931]. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].
Pharmacokinetics
- Absorption
- Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg [L931]. The stable concentrations of the drug are reached after two days of initial treatment [A20331].
- Distribution
- The apparent volume of distribution (Vd/F) of dienogest is 40 L [L931].
- Metabolism
- Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4. The metabolites are pharmacologically inactive and rapidly eliminated from the plasma.
- Elimination
Clearance
The metabolic clearance rate from serum (Cl/F) is 64 mL/min [L931].
Toxicity
Oral LD50 in mouse is 4 mg/kg [MSDS]. In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma [L932]. These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity [L932]. Dienogest does not display genotoxic potential.
Active Ingredient/Synonyms
17-alpha-Cyanomethyl-17-beta-hydroxy-estra-4,9(10)-dien-3-one | 17alpha-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile | BAY 86-5258 | Dienogestril | Dienogestum | Endometrion | Dienogest |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Estradiol (also known as E2 or 17β-estradiol) is a naturally occurring hormone that circulates endogenously within the human body. It is the most potent form of mammalian estrogenic steroids and acts as the major female sex hormone. As such, estradiol plays an essential role in the regulation of the menstrual cycle, in the development of puberty and secondary female sex characteristics, as well as in ageing and several hormonally-mediated disease states. Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. Estradiol is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen production such as menopausal and peri-menopausal symptoms as well as hypoestrogenism. It is also used in transgender hormone therapy, as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol), and is sometimes used for the palliative treatment of some hormone-sensitive cancers like breast and prostate cancer. Estradiol is available in a number of formulations including oral, transdermal, and injectable. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women [FDA Label]. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). It is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter the systemic circulation and exert its estrogenic effects [A12102]. Esterification of estradiol aims to improve absorption after oral administration (such as with Estradiol valerate) or to sustain release from intramuscular depot injections (such as with Estradiol Cypionate) through improved lipophilicity [T84]. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as a number of concerns were raised regarding the use of estrogen [A31626]. Specifically, the combined estrogen–progestin arm was discontinued after approximately five years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events [A31627]. Following extensive critique of the WHI results in the years following its release, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years post-menopause) in low doses, and in women without a history of breast cancer or at increased risk of cardiovascular or thromboembolic disease [A31628]. Notably, use of estrogen for menopausal symptoms should always be accompanied by a progestin component due to estrogen's effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer in the long-term. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination Oral Contraceptive Pills (OCPs). Ethinyl Estradiol differs from Estradiol in that it has improved biovailability and greater resistance to metabolism, making it more suitable for oral administration.
Indication
Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of post-menopausal osteoarthritis. It is also used for the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Mechanism of Action
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
Pharmacokinetics
- Absorption
- 43%
- Distribution
- Metabolism
- Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.
- Elimination
Active Ingredient/Synonyms
(17β)-estra-1,3,5(10)-triene-3,17-diol | 17beta oestradiol | 17β-estra-1,3,5(10)-triene-3,17-diol | 17β-estradiol | 17β-oestradiol | beta-Estradiol | cis-Estradiol | Estradiol | Estradiol-17beta | Estradiolum | Estradiol |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Dienogest is an orally-active semisynthetic progestogen which also possesses the properties of 17α-hydroxyprogesterone. It is a derivative of 19-nortestosterone and has antiandrogenic properties. It is primarily used as a contraceptive in combination with ethinylestradiol, or in other combination form pills approved in United States and Europe however it is not available in the US by itself. In Europe, Australia, Malaysia, Singapore and Japan, dienogest single therapy is an approved treatment for endometriosis to alleviate painful symptoms of endometriosis and reduce endometriotic lesions [A20330]. Dienogest is commonly marketed as Visanne, Natazia and Qlaira.
Indication
Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol.
Mechanism of Action
Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use [A20331]. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium [L932]. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue [L931]. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].
Pharmacokinetics
- Absorption
- Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg [L931]. The stable concentrations of the drug are reached after two days of initial treatment [A20331].
- Distribution
- The apparent volume of distribution (Vd/F) of dienogest is 40 L [L931].
- Metabolism
- Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4. The metabolites are pharmacologically inactive and rapidly eliminated from the plasma.
- Elimination
Clearance
The metabolic clearance rate from serum (Cl/F) is 64 mL/min [L931].
Toxicity
Oral LD50 in mouse is 4 mg/kg [MSDS]. In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma [L932]. These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity [L932]. Dienogest does not display genotoxic potential.
Active Ingredient/Synonyms
17-alpha-Cyanomethyl-17-beta-hydroxy-estra-4,9(10)-dien-3-one | 17alpha-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile | BAY 86-5258 | Dienogestril | Dienogestum | Endometrion | Dienogest |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Estradiol (also known as E2 or 17β-estradiol) is a naturally occurring hormone that circulates endogenously within the human body. It is the most potent form of mammalian estrogenic steroids and acts as the major female sex hormone. As such, estradiol plays an essential role in the regulation of the menstrual cycle, in the development of puberty and secondary female sex characteristics, as well as in ageing and several hormonally-mediated disease states. Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. Estradiol is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen production such as menopausal and peri-menopausal symptoms as well as hypoestrogenism. It is also used in transgender hormone therapy, as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol), and is sometimes used for the palliative treatment of some hormone-sensitive cancers like breast and prostate cancer. Estradiol is available in a number of formulations including oral, transdermal, and injectable. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women [FDA Label]. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). It is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter the systemic circulation and exert its estrogenic effects [A12102]. Esterification of estradiol aims to improve absorption after oral administration (such as with Estradiol valerate) or to sustain release from intramuscular depot injections (such as with Estradiol Cypionate) through improved lipophilicity [T84]. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as a number of concerns were raised regarding the use of estrogen [A31626]. Specifically, the combined estrogen–progestin arm was discontinued after approximately five years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events [A31627]. Following extensive critique of the WHI results in the years following its release, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years post-menopause) in low doses, and in women without a history of breast cancer or at increased risk of cardiovascular or thromboembolic disease [A31628]. Notably, use of estrogen for menopausal symptoms should always be accompanied by a progestin component due to estrogen's effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer in the long-term. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination Oral Contraceptive Pills (OCPs). Ethinyl Estradiol differs from Estradiol in that it has improved biovailability and greater resistance to metabolism, making it more suitable for oral administration.
Indication
Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of post-menopausal osteoarthritis. It is also used for the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Mechanism of Action
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
Pharmacokinetics
- Absorption
- 43%
- Distribution
- Metabolism
- Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.
- Elimination
Active Ingredient/Synonyms
(17β)-estra-1,3,5(10)-triene-3,17-diol | 17beta oestradiol | 17β-estra-1,3,5(10)-triene-3,17-diol | 17β-estradiol | 17β-oestradiol | beta-Estradiol | cis-Estradiol | Estradiol | Estradiol-17beta | Estradiolum | Estradiol |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.