Dienogest was discovered in 1979 and was introduced for medical use in 1995.[17][18][19] Additional formulations of dienogest were approved between 2007 and 2010.[10][20] It is sometimes referred to as a "fourth-generation" progestin.[21][22] Dienogest is marketed widely throughout the world.[13] It is available as a
generic medication.[23]
Birth control pills containing dienogest and estradiol valerate are approved in the
United States for the treatment of
menorrhagia (heavy menstrual bleeding).[12]
Birth control pills containing
estradiol valerate/dienogest are associated with a significantly increased risk of
venous thromboembolism.[35] However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing
ethinylestradiol and a progestin.[35]
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
thyroidmetabolism.[11]
Interactions
Dienogest is
metabolized mainly by the
cytochrome P450enzymeCYP3A4,[3][10] and for this reason,
inhibitors and
inducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it.[10] (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.[10]
Notes: Values are percentages (%). Reference
ligands (100%) were
promegestone for the
PRTooltip progesterone receptor,
metribolone for the
ARTooltip androgen receptor,
estradiol for the
ERTooltip estrogen receptor,
dexamethasone for the
GRTooltip glucocorticoid receptor,
aldosterone for the
MRTooltip mineralocorticoid receptor,
DHTTooltip dihydrotestosterone for
SHBGTooltip sex hormone-binding globulin, and
cortisol for
CBGTooltip Corticosteroid-binding globulin. Sources:[1]
Dienogest has been described as "special" progestogen, possessing low or moderate
antigonadotropic efficacy but strong or very strong
endometrial efficacy.[2][7] In relation to its endometrial activity, dienogest is said to be one of the strongest progestogens available.[2] The high endometrial activity of dienogest underlies its ability to stabilize the
menstrual cycle when combined with either ethinylestradiol or estradiol valerate (which has lower relative effects on the uterus compared to ethinylestradiol) in birth control pills, and also its use in the treatment of endometriosis.[2] 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.[2] 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.[1] 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.[2] The absence of
withdrawal bleeding, otherwise known as "silent menstruation", also may occur.[2] 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
gonane19-nortestosterone progestins like
levonorgestrel.[36]
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.[2]
The minimum effective dose of oral dienogest required to inhibit
ovulation is 1 mg/day.[2][1] 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.[2][1] 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.[2] At this dosage, estradiol levels are reduced to early
follicular phase levels of about 30 to 50 pg/mL.[2] Such levels are insufficient for reactivation of endometrioses, but are sufficient to avoid
menopausal-like symptoms such as
hot flashes and
bone loss.[2] This is in contrast to
gonadotropin-releasing hormone analogues (GnRH analogues), which suppress estradiol levels to lower concentrations and readily induce menopausal-like symptoms.[2]
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.[2]
Antigonadotropic effects
Dienogest has been found to suppress testosterone levels in men by 43% at 2 mg/day, 70% at 5 mg/day, and 81% at 10 mg/day.[37][38] The suppression of testosterone levels with 10 mg/day dienogest was comparable to that with 10 mg/day
cyproterone acetate.[38][37] In general, progestogens are able to suppress testosterone levels in men by a maximum of about 70 to 80% at sufficiently high doses.[39][40][41][42][43]
Dienogest is rapidly
absorbed with
oral administration and has high
bioavailability of approximately 90%.[3]Peak levels of dienogest occur within approximately 2 hours after an oral dose.[7] The pharmacokinetics of dienogest are linear; single oral doses of dienogest were found to result in maximal levels of 28 ng/mL with 1 mg, 54 ng/mL with 2 mg, 101 ng/mL with 4 mg, and 212 ng/mL with 8 mg.[7] The corresponding
area-under-the-curve levels were 306, 577, 1153, and 2293 ng/mL, respectively.[7] Dienogest reaches
steady-state concentrations within 6 days of continuous administration, and does not accumulate in the body.[7][3] The
plasma protein binding of dienogest is 90%, with a relatively high free fraction of 10%.[7] It is exclusively bound to
albumin, with no binding to SHBG or
corticosteroid-binding globulin.[2][7][3] The lack of affinity of dienogest for SHBG is in contrast to most other 19-nortestosterone progestins.[2] The
volume of distribution of dienogest is relatively low at 40 L.[7]
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.[48] 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).[51][52] 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.[53] 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.[54][55]
History
Dienogest was synthesized in 1979 in
Jena,
Germany under the leadership of Kurt Ponsold, was initially referred to as STS-557.[17][18] It was found that its potency was 10 times that of
levonorgestrel.[56] The first product on the market to contain dienogest was a combined birth control pill (with ethinylestradiol), Valette, introduced in 1995 and made by
Jenapharm.[19] 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.[10] Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.[20]
Society and culture
Generic names
Dienogest is the
generic name of the drug and its
INNTooltip International Nonproprietary Name,
USANTooltip United States Adopted Name,
BANTooltip British Approved Name, and
JANTooltip Japanese Accepted Name, while diénogest is its
DCFTooltip Dénomination Commune Française.[47][13] It is also known by its synonyms dienogestril and cyanomethyldienolone as well as by its numerous former developmental code names including BAY 86-5258, M-18575, MJR-35, SH-660, SH-T00660AA, STS-557, and ZK-37659.[47][13]
Brand names
Dienogest is marketed in combination with
estradiol valerate as a
birth control pill primarily under the brand names Natazia and Qlaira and in combination with
ethinylestradiol as a birth control pill primarily under the brand name Valette, although these combinations are marketed under numerous other brand names as well.[13] In the case of the dienogest and estradiol valerate birth control pill, these other brand names include Gianda and Klaira.[13] Dienogest is also marketed in combination with estradiol valerate for use in
menopausal hormone therapy under a variety of brand names including Climodien, Climodiène, Estradiol Valeraat / Dienogest, Klimodien, lafamme, Lafleur, Mevaren, Valerix, and Velbienne.[13] Dienogest is marketed as a standalone medication for the treatment of
endometriosis primarily under the brand name Visanne, but is also available under the brand names Alondra, Dinagest, Disven, Visabelle, and Visannette in various countries.[13]
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