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Dienogest (DNG) is a fourth-generation progestin, being extensively used in a wide variety of clinical settings in gynecology. In order to write this comprehensive review, a literature search was performed to identify systematic reviews and randomized trials involving DNG. Databases searched included MEDLINE, PUBMED, Embassy and the Cochrane library. The term ‘dienogest’ was associated with the following search terms: ‘endometriosis’, ‘contraception’, ‘hormone replacement therapy’, ‘safety’, ‘efficacy
Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. DNG also has some properties
typical of other progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity [1,2]. DNG has no antiestrogenic activity, which is explained in its role in the treatment of endometriosis . It is exclusively protein bound (albumin-90%, free-10%). The lack of DNG binding to sex hormone binding globulin means it does not displace testosterone, resulting in the androgenic effects observed with other progestins. It is metabolized by hydroxylation and conjugation, predominantly in the liver . DNG is available in the dose of 2mg/day (Figure1) (Table 1).
In a safety cohort of 727 women , the most frequently
reported adverse effect with DNG was headache (9%), acne
(5.1%), nausea (4.2%), weight gain (3.6%). Changes in menstrual
bleeding patterns were also common in these trials. After 9-12
months of use, bleeding was regularized in 22%, but 28% reported
amenorrhea, oligomenorrhoea in 24% and polymorphous in 2.7%.
Mechanism of action: DNG reduces endometriotic lesions
through a number of biological mechanisms. It is associated with
relatively moderate inhibition of gonadotrophin secretion, leading
to a modest reduction in the endogenous production of estradiol5.
When given continuously, dienogest induces a hypoestrogenic,
hypergestagenic local endocrine environment, causing a
decidualization of endometrial tissue followed by atrophy of the
endometriotic lesions. In exploratory models of endometriosis,
dialogist also demonstrates antiproliferative, anti-inflammatory,
and anti-angiogenic effects [6-9].
Pain relief: A large RCT9 (N=252) was carried out, in which
124 women were randomised to receive DNG and 128 women
received leuprolide acetate (LA). The VAS (Visual analog scale)
score was selected as the primary efficacy variable in this study
because the VAS is an appropriate and well-established tool for
the measurement of pelvic pain associated with endometriosis
. Absolute reductions in VAS score from baseline to week
24 were 47.5mm with DNG and 46.0mm with LA. This finding
was of high clinical relevance, as pelvic pain is one of the most
important symptoms of endometriosis and because agents in the
GnRh agonist class are widely considered a reference standard
treatment for improving these symptoms .
Hypoestrogenic effects: It is a known fact that GnRH agonists
produce hypogonadotrophic hypogonadism. An interesting
hypothesis was proposed by Barbieri , way back in 1992. It
stated that, ‘a concentration of estradiol that will partially prevent
bone loss may not stimulate endometrial growth’. DNG maintains
estrogen levels within the therapeutic window for endometriosis,
that is 30-50pg/ml. Hence, the incidence of hypoestrogenic effects
is less with DNG when compared to LA9.
Bone Mineral Density (BMD) reduction: GnRH agonists
cause significant loss in trabecular and cortical bone, particularly
lumbar spine and femoral neck. This may even exceed 1% per
month . On the other hand, DNG showed no change in the
mean lumbar BMD during the treatment period9, demonstrating
minimal changes in bone turnover/bone resorption markers.
Dienogest as the first-choice progestin for the medical
therapy of symptomatic endometriosis does not confer additional
benefits compared with norethindrone acetate in terms of pain
relief, health-related quality of life, or sexual functioning .
Effectiveness of either of the progestins is greatly affected by
Fertility considerations with DNG use based on the current
evidence, dienogest causes complete inhibition of ovulation at a
daily dose of 2mg [15,16]. However, dienogest monotherapy was
not developed as a contraceptive, and women taking dienogest
as a treatment for endometriosis are advised to use nonhormonal
methods of contraception . The ovarian activity
resumes rapidly (range 1-43 days) after cessation of dienogest
. Successful pregnancy has been reported in women with
endometriosis following the cessation of dienogest treatment 2mg
daily for duration of up to 1 year [18,19].
Long term safety profile of DNG in endometriosis: Two large
trials have been performed in Europe and Japan, to investigate
the role of DNG in the long-term treatment of endometriosis. The
European trial offered DNG for an overall treatment period of 65
weeks . The intensity of pain showed significant, sustained
improvement during this long-term study. In addition, during the
24-week treatment free period following the long term study, visual
analog scores increased only moderately, suggesting that DNG
induces a beneficial effect that may persist even after treatment
cessation. The results of the European study were supported by a
52 week, non-randomized trial of DNG conducted in Japan on 135
women with confirmed endometriosis . Patient satisfaction
with DNG at the end of treatment was high, with 88.9% of women
responding that they were ‘’certainly willing” or “would prefer” to
use DNG again.
Estradiol valerate/dienogest (E2V/DNG) is a 4-phasic oral
contraceptive approved for the prevention of pregnancy. The
4-phasic design allows for acceptable cycle control and in efficacy
trials of estradiol valerate/dienogest in women aged 18-35 years,
the Pearl Index ranged from 0.40 to 1.64, a range comparable to
that of other combination oral contraceptives .
In most combination oral contraceptives, the estrogen
component is responsible for providing cycle control and
stabilizing the endometrium for an acceptable bleeding pattern.
E2V, unlike ethinyl estradiol, did not provide an adequate level of
endometrial stability, as evidenced by breakthrough bleeding rates
in preliminary studies . Hence, E2V.containing combination
oral contraceptives did not reach the market until this novel
combination of E2V and DNG was evaluated .
This combination integrates an estrogen step-down and
a progestin step-up approach in a quadri-phasic regimen
(Figure 2). The American College of Obstetrics and Gynecology recommends that patients with anovulatory or ovulatory bleeding
be treated with a combination oral contraceptive if they require
contraception [23,24]. E2V/DNG is an appropriate first choice in
heavy menstrual bleeding, for most premenopausal women who
have a need for contraception, do not have contraindications to
estrogen therapy, and do not desire LNG-IUD insertion. Use of
E2V/DNG for six months has led to significant reduction in heavy
menstrual bleeding with an average 65% reduction in mean blood
A combination of 2mg estradiol valerate with 2mg dienogest
(E2V/DNG) is the first continuous combined postmenopausal
Hormone Replacement Therapy (HRT) preparation to contain
a progestogen with substantial anti-androgenic activity. A study
of its clinical efficacy and safety in a comparative study versus a
combination of 2mg estradiol with 1mg norethisterone acetate
(E2/NETA) has shown both preparations to be highly effective
in achieving a rapid response in women with postmenopausal
symptoms . E2V/DNG is a novel HRT preparation that has a
highly favorable bleeding profile.
Dienogest is a novel drug in the treatment of endometriosis,
with an efficacy comparable to GnRh agonists. It is orally
administered (unlike GnRh agonists) and more reasonably priced.
Its role in contraception and HRT seems promising.