Alone: Dinagest, Visanne|
With EV: Natazia, Qlaira
With EE: Valette
|Synonyms||Dienogestril; Cyanomethyldienolone; BAY-865258; Endometrion; M-18575; MJR-35; SH-660; SH-T00660AA; STS-557; ZK-37659; 17α-Cyanomethyl-δ9-19-nortestosterone; 17α-Cyanomethylestra-4,9(10)-dien-17β-ol-3-one; 17β-Hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-nitrile|
|AHFS/Drugs.com||International Drug Names|
|Drug class||Progestin; Progestogen; Steroidal antiandrogen|
|Elimination half-life||10 hours|
|Chemical and physical data|
|Molar mass||311.42 g/mol|
|3D model (JSmol)|
|Boiling point||549 °C (1,020 °F)|
|(what is this?)|
Dienogest, sold under the brand names Natazia and Qlaira among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. The medication is available both alone and in combination with estrogens. It is taken by mouth.
Side effects of dienogest include menstrual irregularities, headaches, nausea, breast tenderness, depression, acne, and others. Dienogest is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has some antiandrogenic activity, which may help to improve androgen-dependent symptoms like acne, and has no other important hormonal activity.
Dienogest was discovered in 1979 and was introduced for medical use in 1995. Additional formulations of dienogest were approved between 2007 and 2010. It is sometimes referred to as a "fourth-generation" progestin. Dienogest is marketed widely throughout the world. It is available as a generic medication.
- 1 Medical uses
- 2 Side effects
- 3 Interactions
- 4 Pharmacology
- 5 Chemistry
- 6 History
- 7 Society and culture
- 8 Research
- 9 References
- 10 External links
Dienogest is used primarily as an oral contraceptive in combination with ethinylestradiol under the brand name Valette. It is given as a tablet containing 2 mg of dienogest and 30 μg of ethinylestradiol. The drug is also available in a quadriphasic oral contraceptive pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia.
Dienogest is also approved under the brand names Visanne and Dinagest in various countries such as European countries, Australia, Malaysia, Singapore, and Japan for the treatment of endometriosis. It has been shown to be equally effective as leuprorelin, which is a second-line medication against endometriosis.
- Dienogest 1 mg oral tablets (Dinagest) and 2 mg oral tablets (Valette) – indicated for endometriosis
- Dienogest 2 mg and estradiol valerate 3 mg oral tablets (Natazia) – indicated for contraception and menorrhagia
- Dienogest 2 to 3 mg and estradiol valerate 1 to 3 mg oral tablets (Qlaira) – indicated for contraception
- Dienogest 2 mg and ethinylestradiol 30 µg oral tablets (Valette) – indicated for contraception
- Dienogest 2 mg and estradiol valerate 1 or 2 mg oral tablets (Lafamme) – indicated for menopausal hormone therapy
The availability of these formulations differs by country.
Side effects associated with dienogest are the same as those expected of a progestogen. They include menstrual irregularities, headaches, nausea, breast tenderness, depression, acne, weight gain, flatulence, and others. Dienogest produces no androgenic side effects and has little effect on metabolic and lipid hemostatic parameters. In safety studies, dienogest has been assessed in women with endometriosis at a dosage of 20 mg/day for up to 24 weeks and produced no clinically relevant effects on lipid metabolism, liver enzymes, the coagulatory system, or thyroid metabolism.
Dienogest is metabolized mainly by the cytochrome P450 enzyme CYP3A4, and for this reason, inhibitors and inducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it. (For a list of CYP3A4 inhibitors and inducers, see here.) The strong CYP3A4 inhibitors ketoconazole and erythromycin have been found to increase exposure to dienogest by up to 3-fold, whereas the strong CYP3A4 inducer rifampicin (rifampin) was found to decrease steady-state and area-under-curve concentrations of dienogest by 50% and 80%, respectively.
Dienogest is an agonist of the progesterone receptor (PR) and hence is a progestogen. It has relatively low affinity for the PR in vitro in human uterus tissue, about 10% that of progesterone. In spite of its relatively weak affinity for the PR however, the medication does not appear to be a prodrug and it shows strong progestogenic effects on the endometrium. Dienogest is said to be one of the only 19-nortestosterone derivative progestins that does not have androgenic properties. In fact, it is actually an antagonist of the androgen receptor (AR) and hence has antiandrogenic activity, said to be about 30 to 40% of that of cyproterone acetate, and may be able to improve androgen-dependent symptoms such as acne and hirsutism. The drug does not interact with the estrogen receptor, the glucocorticoid receptor, or the mineralocorticoid receptor and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity.
|Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG.|
Inhibition of ovulation
The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day. The inhibition of ovulation by dienogest reportedly occurs mainly via peripheral action as opposed to central action on gonadotropin secretion.
Oral treatment of dienogest 2 mg/day in cyclical women reduced serum progesterone levels to anovulatory levels, however serum levels of luteinizing hormone and follicle-stimulating hormone were not significantly altered.
Dienogest is rapidly absorbed and has high bioavailability of approximately 90%. It reaches steady-state concentrations after two days of administration and does not accumulate in the body. The plasma protein binding of dienogest is 90% and it is exclusively bound to albumin, with no binding to sex hormone-binding globulin or corticosteroid-binding globulin. The drug is metabolized in the liver mainly by CYP3A4. The elimination half-life of dienogest is 10 hours. It is eliminated mainly in the urine, both as sulfate and glucuronide conjugates and as free steroid.
Dienogest, also known as 17α-cyanomethyl-δ9-19-nortestosterone or as 17α-cyanomethylestra-4,9-dien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is a member of the estrane subgroup of the 19-nortestosterone family of progestins, but unlike other 19-nortestosterone progestins, is not a derivative of norethisterone (17α-ethynyl-19-nortestosterone). This is because it uniquely possesses a cyanomethyl group at the C17α position rather than the usual ethynyl group. It is also unique among most 19-nortestosterone progestins in that it has a double bond between the C9 and C10 positions. Dienogest is the C17α cyanomethyl derivative of the anabolic–androgenic steroid (AAS) dienolone, as well as the C17α cyanomethyl analogue of the AAS methyldienolone (17α-methyldienolone) and ethyldienolone (17α-ethyldienolone).
In terms of structure–activity relationships, the C17α cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity relative to other 19-nortestosterone progestins. A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α substitutions such as topterone (propyltestosterone) (compare to the AAS ethyltestosterone and methyltestosterone) and allylestrenol (compare to the AAS ethylestrenol). Studies with steroids similar to dienogest (e.g., dienolone) have found that the introduction of a double bond between the C9 and C10 positions is associated with similar/almost unchanged affinity for the PR and AR. On the other hand, the C9(10) double bond of dienogest appears to inhibit metabolism via 5α-reductase and/or 5β-reductase, which is the major metabolic route for other 19-nortestosterone progestins like norethisterone, norgestrel, and etonogestrel, and this may serve to improve the metabolic stability and potency of dienogest.
Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Kurt Ponsold, was initially referred to as STS-557. It was found that its potency was 10 times that of levonorgestrel. The first product on the market to contain dienogest was a combined oral contraceptive pill (with ethinylestradiol), Valette, introduced in 1995 and made by Jenapharm. In 2007, dienogest was introduced as Dinagest in Japan for the treatment of endometriosis, and it was subsequently marketed for this indication as Visanne in Europe and Australia in December 2009 and April 2010, respectively. Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.
Society and culture
Dienogest is marketed for use as an oral contraceptive in combination with estradiol valerate under the brand names Natazia and Qlaira and in combination with ethinylestradiol under the brand name Valette, and is marketed by itself under the brand names Visanne and Dinagest) for the treatment of endometriosis in Europe, Australia, and Japan. It is also marketed under a variety of other, lesser-known brand names.
Dienogest is available both alone and in combination with estradiol or ethinylestradiol throughout much of the world, including (but not limited to) Canada and many European, South American, and Southeast Asian countries. It is available only in combination with an estrogen and not as a standalone drug in the United States and the United Kingdom.
- Bińkowska, Małgorzata; Woroń, Jarosław (2015). "Progestogens in menopausal hormone therapy". Menopausal Review. 14 (2): 134–143. doi:10.5114/pm.2015.52154. ISSN 1643-8876. PMC . PMID 26327902.
[...] In addition to a very fast absorption rate, dienogest exhibits a very high bioavailability of around 90%. It is bound to albumins in 90%, and around 10% is in a free form. It binds neither to SHBG, nor CBG. Its metabolites are inactive and rapidly excreted. The half-life is 10 hours. Stable concentrations are achieved after two days of treatment. Dienogest does not accumulate in the body. It demonstrates a poor affinity to the PR, but has a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use. It shows antagonist activity by binding to the AR, and hence produces an antiandrogenic action equivalent to ca. 40% of the effect induced by cyproterone acetate. Dienogest does not interact with the GR, MR or ER. [...] In vivo, it has a powerful progestagenic and moderate antigonadotropic activity, without any androgenic, glucocorticoid or mineralocorticoid effects. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. Consequently, dienogest is believed to have a weak central antigonadotropic action, but a potent direct peripheral ovulation-inhibiting effect . [...] Dienogest is metabolized chiefly via the CYP3A4 isoenzyme. [...]
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Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/dienogest), which is a newer four-phasic pack that contains dienogest.
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