Dienogest

Contraception

Dienogest is used primarily as a contraceptive in combination with ethinylestradiol. It is given as a tablet containing 2 mg of dienogest and 30 μg of ethinylestradiol. Dienogest 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. This formulation is also approved for the treatment of heavy menstrual bleeding.

Endometriosis

Dienogest is also approved in Europe, 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.

Side effects

Adverse effects associated with dienogest are the same as those expected of a progestogen. These include weight gain, increased blood pressure, breast tenderness and nausea. It produces no androgenic side effects and has little effect on metabolic and lipid haemostatic parameters.

Interactions

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.

Pharmacology

Dienogest has relatively low affinity for the progesterone receptor (PR) in vitro in human uterus tissue, about 10% that of progesterone. In spite of its relatively weak affinity for the PR, the drug 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 actually has antiandrogen activity, about 30–40% of that of cyproterone acetate, and can improve androgenic symptoms such as acne and hirsutism. The drug does not interact with the estrogen, glucocorticoid, or mineralocorticoid receptor, and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity. However, it has limited impact on Gonadotropin Releasing Hormone, and thus does not lower LH significantly compared to other progestins.

Metabolites of dienogest, such as 9α,10β-dihydrodienogest and 3,5α-tetrahydrodienogest, show greater affinity for the PR and AR than does dienogest itself (see the table to the right).

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 are not significantly altered.

Pharmacokinetics

Dienogest is rapidly absorbed and has high bioavailability of approximately 90%. It is exclusively protein-bound to albumin (90%, with the remaining 10% being free), and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin. The drug is metabolized in the liver mainly by CYP3A4. Its metabolites are said to be inactive and to be rapidly excreted. The terminal half-life of dienogest is 10 hours. It reaches steady-state concentrations after 2 days of administration and does not accumulate in the body.

Chemistry

Dienogest is an estrane (C18) steroid and 17α-substituted 19-nortestosterone (estr-4-en-17β-ol-3-one) derivative. It is also known by the chemical names 17α-cyanomethyl-19-nor-δ⁹-testosterone and 17α-cyanomethylestra-4,9-dien-17β-ol-3-one. Dienogest is the 17α-cyanomethylated derivative of the anabolic-androgenic steroid (AAS) dienolone, as well as the 17α-cyanomethyl variant of the AAS methyldienolone (17α-methyldienolone) and ethyldienolone (17α-ethyldienolone). It is unique among 19-nortestosterone progestins in that it possesses a cyanomethyl group at the C17α position (instead of the typical ethynyl group), and is also unique among most 19-nortestosterone progestins in that it has a double bond between the C9 and C10 positions.

Structure-activity relationships

The 17α-cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity. A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α chains such as topterone (propyltestosterone) (compare to ethyltestosterone and methyltestosterone) and allylestrenol (compare to 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.

History

Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Prof. 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.

Generic name

Dienogest is the INN, USAN, BAN, and JAN of the drug.

Availability

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.