Dienogest
Dienogest, sold under the brand name Visanne 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. Dienogest 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, and acne, among 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 is a unique progestogen, with strong effects in the uterus. The medication 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.
Medical uses
Birth control
Dienogest is used primarily in birth control pills in combination with ethinylestradiol under the brand name Valette. It is also available in a quadriphasic birth control pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia.Endometriosis
Dienogest is approved as a standalone medication under several brand names in many countries such as European nations, Israel, Australia, Japan, Singapore, and Malaysia for the treatment of endometriosis. It has been found to be equally effective as gonadotropin-releasing hormone agonists, such as leuprorelin, in the treatment of endometriosis.Heavy periods
Birth control pills containing dienogest and estradiol valerate are approved in the United States for the treatment of menorrhagia.Menopausal symptoms
Dienogest is used in combination with estradiol valerate in the treatment of menopausal symptoms in certain countries such as Germany and the Netherlands.Available forms
Dienogest is available both alone and in combination with estrogens. The following formulations are available:- Dienogest 1 mg oral tablets and 2 mg oral tablets – indicated for endometriosis
- Dienogest 2 mg and estradiol valerate 3 mg pills – indicated for contraception and menorrhagia
- * 2 orange pills each containing 3 mg estradiol valerate
- * 5 pink pills each containing 2 mg estradiol valerate and 2 mg dienogest
- * 17 yellow pills each containing 2 mg estradiol valerate and 3 mg dienogest
- * 2 red pills each containing 1 mg estradiol valerate
- * 2 white pills
- Dienogest 2 to 3 mg and estradiol valerate 1 to 3 mg oral tablets – indicated for contraception
- * Each dark yellow active tablet contains 3 mg estradiol valerate
- * Each medium red active tablet contains 2 mg estradiol valerate and 2 mg dienogest
- * Each light yellow active tablet contains 2 mg estradiol valerate and 3 mg dienogest
- * Each dark red active tablet contains 1 mg estradiol valerate
- Dienogest 2 mg and ethinylestradiol 30 μg oral tablets – indicated for contraception
- Dienogest 2 mg and estradiol valerate 1 or 2 mg oral tablets – indicated for menopausal hormone therapy
Contraindications
s of dienogest include active venous thromboembolism, previous or current cardiovascular disease, diabetes with cardiovascular complications, previous or current severe liver disease or tumors, hormone-dependent cancers such as breast cancer, and undiagnosed vaginal bleeding.Side effects
s 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.Birth control pills containing estradiol valerate/dienogest are associated with a significantly increased risk of venous thromboembolism. However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin.
Overdose
In safety studies, dienogest has been assessed in women with endometriosis at high doses of as much as 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.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. 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 was found to decrease steady-state and area-under-curve concentrations of dienogest by 50% and 80%, respectively.Pharmacology
Pharmacodynamics
Dienogest has progestogenic activity, possibly some antiprogestogenic activity, and has antiandrogenic activity. The medication does not interact with the estrogen receptor, the glucocorticoid receptor, or the mineralocorticoid receptor, and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity. Because of its relatively high selectivity as a progestogen, dienogest may have favorable safety and tolerability compared to various other progestins.Progestogenic activity
Dienogest is an agonist of the progesterone receptor, and hence is a progestogen. It has relatively weak affinity for the PR in vitro in human uterine tissue, about 10% that of progesterone. Despite its low affinity for the PR however, dienogest has high progestogenic activity ''in vivo''. In addition, although its metabolites, such as 9α,10β-dihydrodienogest and 3α,5α-tetrahydrodienogest, have greater affinity for the PR than does dienogest itself, the medication is not considered to be a prodrug.| Progestogen | / ratio | ||
| Chlormadinone acetate | 25 | 1.7 | 1.5 |
| Cyproterone acetate | 20 | 1.0 | 2.0 |
| Dienogest | 6 | 1.0 | 0.6 |
| Norethisterone | 120 | 0.4 | 30 |
| Norethisterone acetate | 50 | 0.5 | 10 |
| Norgestimate | 7 | 0.2 | 3.5 |
| Levonorgestrel | 5 | 0.06 | 8.3 |
| Desogestrel | 2 | 0.06 | 3.3 |
| Gestodene | 3 | 0.04 | 7.5 |
| Drospirenone | 50 | 2.0 | 2.5 |
| Nomegestrol acetate | 100 | 5.0 | 2.0 |
Dienogest has been described as "special" progestogen, possessing low or moderate antigonadotropic efficacy but strong or very strong endometrial efficacy. In relation to its endometrial activity, dienogest is said to be one of the strongest progestogens available. The high endometrial activity of dienogest underlies its ability to stabilize the menstrual cycle when combined with either ethinylestradiol or estradiol valerate in birth control pills, and also its use in the treatment of endometriosis. The combination of most other progestins with estradiol or an estradiol ester like estradiol valerate as birth control pills was unsatisfactory due to a high incidence of irregular menstrual bleeding. This is a property that ethinylestradiol does not share with estradiol, because of its resistance to metabolism in the endometrium and hence its greater relative effects in this part of the body. In contrast to other progestins, due to its high endometrial efficacy, the combination of dienogest with estradiol valerate in birth control pills is able to prevent breakthrough bleeding, and is uniquely able to treat heavy menstrual bleeding. The absence of withdrawal bleeding, otherwise known as "silent menstruation", also may occur. Dienogest has antiovulatory potency that is similar to that of 17α-hydroxyprogesterone derivatives like cyproterone acetate but endometrial potency that is much stronger and similar to that of gonane 19-nortestosterone progestins like levonorgestrel.
Unlike other progestogens, except in the case of its strong effects in the uterus, dienogest has been described as lacking antiestrogenic effects, and does not antagonize beneficial effects of estradiol, for instance in the metabolic and vascular systems.
Dienogest showed some possible antiprogestogenic activity in one animal bioassay when administered before but not at the same time as progesterone.
The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day. The inhibition of ovulation by dienogest occurs mainly via a direct peripheral action in the ovary of inhibiting folliculogenesis as opposed to a central action of inhibiting gonadotropin secretion. Oral therapy with 2 mg/day dienogest in cyclical premenopausal women reduced serum progesterone levels to anovulatory levels, but circulating levels of luteinizing hormone and follicle-stimulating hormone were not considerably affected. At this dosage, estradiol levels are reduced to early follicular phase levels of about 30 to 50 pg/mL. Such levels are insufficient for reactivation of endometrioses, but are sufficient to avoid menopausal-like symptoms such as hot flashes and bone loss. This is in contrast to gonadotropin-releasing hormone analogues, which suppress estradiol levels to lower concentrations and readily induce menopausal-like symptoms.
Dienogest appears to have similar effects in the breasts as norethisterone acetate, and may likewise increase the risk of breast cancer when combined with an estrogen in postmenopausal women, although this has yet to be confirmed in clinical studies.