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Open Access Journal of Contraception 2013:4 39–50
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REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/OAJC.S50693
Comparison of the pharmacologic and clinical
proles of new combined oral contraceptives
containing estradiol
Jeffrey T Jensen1
Johannes Bitzer2
Marco Serrani3
1Department of Obstetrics and
Gyn eco log y, Oregon Health and
Science University, Portland, OR,
USA; 2Department of Social Medicine
and Psychosomatics, Wome n’s
Hospital, University Hospital of Basel,
Basel, Switzerland; 3Global Medical
Aff air s, Women’s Healthcare, Bayer
HealthCare Pharmaceuticals, Berlin,
Germany
Correspondence: Jeffrey T Jensen
Department of Obstetrics and
Gynecology, Oregon Health and Science
University, 3181 SW Sam Jackson Park
Road, Portland, OR 97239, USA
Tel +1 503 494 5113
Fax +1 503 494 5083
Email jensenje@ohsu.edu
Abstract: Three estradiol (E2)-containing oral contraceptives, estradiol valerate/cyproterone
acetate (E2V/CPA, Femilar®), estradiol valerate/dienogest (E2V/DNG, Qlaira®/Natazia™),
and estradiol/nomegestrol acetate (E2/NOMAC; Zoely®), have received approval for use in
general practice. Only Finnish women currently have access to all three E2-based formulations.
E2/NOMAC is currently approved only in Europe, while E2V/DNG is approved globally. To
assist clinicians counseling women considering use of one of these formulations, we conducted
a review of the published information about the current E2-containing oral contraceptives.
A literature search was conducted using the Ovid interface and a combination of free search
terms relevant to estradiol and oral contraception to identify suitable articles for inclusion in
this review. The available data show that E2V/DNG, E2/NOMAC, and E2V/CPA are all effec-
tive oral contraceptives. While direct comparisons are lacking, indirect evidence suggests that
E2V/DNG and E2/NOMAC may have better bleeding profiles than E2V/CPA. E2V/DNG is
also approved for the treatment of heavy menstrual bleeding. Both E2V/DNG and E2/NOMAC
have minimal influence on hemostatic, lipid, and carbohydrate metabolism parameters, or
induce less change in these parameters relative to ethinylestradiol-based oral contraceptives.
However, the predictive value of these surrogate parameters is a matter of debate, and whether
these differences can be translated into meaningful clinical outcomes needs to be established in
large-scale, post-marketing, prospective, Phase IV cohort studies. Future studies are required
to determine whether E2-based oral contraceptives confer additional benefits compared with
those of ethinylestradiol-based COCs.
Keywords: estradiol valerate, dienogest, nomegestrol acetate, cyproterone acetate
Introduction
Over the last 50 years, refinements in the formulation of combined oral contraceptives
(COCs) have focused on improving their tolerability and safety. Primary modifications
include a reduced ethinylestradiol (EE) dose and incorporation of new progestins with
improved selectivity profiles which are closer in function to natural progesterone.1
Drospirenone (DRSP), dienogest (DNG), and nomegestrol acetate (NOMAC) are the
most recent progestins introduced to the market, and products containing nestorone
and trimegestone are in development.
Although the contraceptive effects of COCs are mainly achieved through
progestin alone, estrogen remains an important component because its inclusion
enhances contraceptive efficacy and helps regulate bleeding. While the type of
progestin and dosing regimen used may affect overall cycle control,2 COCs with
lower EE doses tend to have poorer cycle control (ie, unscheduled bleeding and/
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Jensen et al
or spotting) relative to formulations with the same proges-
tin and a higher EE dose.2–4 Very low-dose EE products
administered in a 24/4 and 26/2 regimen (15 µg in combi-
nation with gestodene 60 µg,5 and 10 µg in combination
with norethindrone acetate 1 mg,6 respectively) have been
approved. Although EE 15 µg/gestodene 60 µg appears to
have acceptable cycle control and tolerability,7,8 no data
are available for EE 10 µg/norethindrone acetate 1 mg.
Although the reduction of the EE dose to less than 50 µg
has greatly improved the cardiovascular safety profile of
combined pills, the benefit of dose reduction to 20 µg or
lower has not been definitively established.9 Even with mod-
ern “low-dose” EE formulations, factors related to hepatic
and carbohydrate metabolism, as well as hemostasis, may
be maintained at an upregulated level. Biological potency
of estrogens depends on ligand-receptor interactions
plus the rate of absorption, distribution, metabolism, and
elimination. For EE, both its receptor binding affinity and
its biological potency with regard to various clinical and
metabolic parameters are usually greater than with estradiol
(E2).10,11 Reliance on the use of EE in COCs has largely
been due to its higher oral bioavailability (38%–48%)
compared with other estrogens.10 Inclusion of a 17α-ethinyl
group on estradiol greatly enhances oral activity due to
inhibition of hepatic metabolism, in particular, reduced
metabolism to weaker estrogens. Oral EE is completely and
rapidly absorbed in the gastrointestinal tract, undergoing
oxidation to yield free hydroxylated and methylated active
metabolites plus sulfate and glucuronide conjugates dur-
ing first-pass metabolism in the gut and liver.12 In contrast,
oral E2 is completely absorbed in the gastrointestinal tract
and undergoes extensive metabolism to less potent estrone
and estrone sulfate during the absorption process and in
the liver.13 As a result, oral bioavailability of estradiol is
typically only about 3%–6%.12
The higher intrinsic estrogenic activity of EE combined
with the reduced degradation and active metabolites results
in more pronounced effects on hepatic metabolism and
hemostatic changes relative to E2. More simply put, oral
EE activates the liver through both a first-pass effect and
recirculation of EE, while hepatic activation of oral E2 occurs
predominantly through first pass. For this reason, even non-
oral routes of EE administration result in dose-related effects
on hepatic globulins.14 It has been hypothesized that using
oral E2 might reduce the relative impact on the hepatic and
hemostatic effects and adverse events associated with EE,
given that activation by recirculation does not occur.15,16
Early attempts to develop E2-containing oral contraceptives
as alternatives to EE-based formulations showed that E2-
containing formulations could achieve effective inhibition of
ovulation and contraception. However, these early formula-
tions were associated with unacceptable bleeding patterns
and, thus, were suspended from further development.17–21 The
bleeding problems associated with these earlier attempts to
incorporate E2 into an oral contraceptive might be explained,
in part, by the activity of 17β-estradiol dehydrogenase.
This enzyme rapidly converts E2 (but not EE) into estrone
(E1),22,23 an estrogen with only weak estrogenic activity that
is unable to maintain stable endometrial proliferation.23
The rate of transformation of E2 to its metabolites may be
influenced by some progestins;13 consequently, progestins
with minimal impact on E2 metabolism and endometrial
stroma stability may improve cycle stability with E2-based
oral contraceptives.24
To date, only three E2-containing oral contraceptives
have received regulatory approval for use in general practice.
These include estradiol valerate/cyproterone acetate (E2V/
CPA; Femilar®, Bayer Oy, Turku, Finland), estradiol valerate/
dienogest (E2V/DNG; Qlaira®/Natazia™, Bayer HealthCare
Pharmaceuticals, Berlin, Germany), and estradiol/nomege-
strol acetate (E2/NOMAC; Zoely®; Theramex Srl, Milan,
Italy). Clinicians and other family planning providers need
informed guidance when counseling their patients about
E2-containing oral contraceptives, because a number of
factors may influence women’s choice. As new data have
become available, this comprehensive review seeks to com-
pare and contrast the pharmacologic and clinical profiles of
E2-containing oral contraceptives.
Methods
A systematic literature search was conducted using Ovid
to search both MEDLINE and EMBASE simultaneously
for clinical studies published up to February 20, 2013
on the three marketed E2-containing COCs (E2V/DNG,
E2/NOMAC, and E2V/CPA). The search strategy combined
free text terms relevant to oral contraception and estradiol
as follows: (beta estradiol OR beta estradiol OR E2 OR
natural estradiol OR natural estradiol) AND contracep*
(where* is a wild character). The titles and abstracts from
the electronic searches were initially assessed for relevant
articles published in English. In addition, the reference lists
of pertinent review articles identified were also examined
for relevant studies not captured by the electronic search.
Studies evaluating the pharmacologic and clinical profiles
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41
Estradiol-containing oral contraceptives
of these E2-containing COCs were chosen for inclusion in
this review.
Approved formulations
and regimens
E2V/CPA is a biphasic preparation taken in a 21/7 cycle regi-
men (E2V 1 mg/CPA 1 mg on days 1–10, E2V 2 mg/CPA 2 mg
on days 11–21, and a 7-day pill-free interval). The rationale
for the biphasic E2V/CPA regimen has not been discussed
in the literature, but phasic regimens are generally used in
order to optimize control of bleeding.
E2V/DNG is taken in a 26/2 cycle, with E2V 3 mg on
days 1–2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/
DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, and
placebo on days 27–28. This specific regimen was estab-
lished as the lowest effective dose of E2V combined with
DNG for efficient ovulation inhibition while maintaining
acceptable bleeding control.25,26 The regimen for E2V/DNG
was designed to provide phased delivery of hormones with
estrogen dominance early in the cycle and progestin domi-
nance from the mid-to-late part of the cycle. Early estrogenic
dominance is thought to allow for initial endometrial pro-
liferation and upregulation of progesterone receptors; this
enhances sensitivity to mid-cyclic progestin action, lead-
ing to endometrial stroma stability at the end of the cycle,
thereby resulting in predictable bleeding.27 The rationale for
estradiol alone towards the end of the cycle and the short
hormone-free interval is to ensure that overall estradiol levels
remain relatively stable throughout each cycle (including the
hormone-free interval).22
E2/NOMAC is a monophasic preparation taken over a
cycle of 24/4 days (E2 1.5 mg/NOMAC 2.5 mg on days 1–24
and placebo on days 25–28). The 2.5 mg dose of NOMAC
was established as the optimum dose needed for ovulation
inhibition. The 1.5 mg E2 dose was selected based on the
dose used in estrogen replacement therapy established to
provide adequate estrogen levels for prevention of osteopo-
rosis in postmenopausal women.28 The rationale behind the
24/4 regimen for E2/NOMAC is based, in part, on the greater
ovarian suppression achieved relative to the conventional
21/7 regimen, which may result in a greater contraceptive
margin and a shorter duration of withdrawal bleeding (com-
pared with traditional 21/7 regimen oral contraceptives), as
well as decreased hormonal fluctuations (particularly for E2)
and associated hormone withdrawal symptoms.29 The bleed-
ing control achieved with E2/NOMAC has been hypothesized
to be due to the ability of NOMAC to maintain endometrial
stability through its minimal impact on endometrial E2 metab-
olism, which ensures sufficient E2 levels in the endometrium
and thus prevents endometrial breakdown.24,30
The absolute bioavailability of E2 following oral
E2/NOMAC administration was estimated to range between
1% and 5%,31 and that following oral E2V/DNG administra-
tion to be about 3%–6%.32 E2V is rapidly hydrolyzed and
converted to 17β-estradiol (E2) during absorption in the
gastrointestinal tract following oral administration (1 mg of
Micronized E2 (1.5 mg)
E2V (2 mg)
121086420
0
10
Time (h)
20
30
40
Mean serum E2 (pg/mL)
Figure 1 Estradiol serum concentration-time curves following single oral doses of micronized E2 (2 mg) and E2V (2 mg). Data obtained from postmenopausal women.
Note: Data used to create the gure taken with permission from Timmer CJ, Geurts TB. Bioequivalence assessment of three differ ent estradiol formulations in postmenopausal
women in an open, randomized, single-dose, 3-way cross-over study. Eur J Drug Metab Pharmacokinet. 1999;24:47–53.33
Abbreviations: E2, estradiol; E2V, estradiol valerate; h, hours.
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Jensen et al
E2V contains 0.76 mg of E2).23 The E2 pharmacokinetic profile
following oral micronized E2 (1.5 mg) appears to be similar
to that following oral E2V (2 mg, Figure 1).33
Indications and pivotal studies
for approved E2-containing COCs
E2V/CPA is available in Finland only and indicated for
women .40 years and for women aged 35–40 years
for whom an oral contraceptive containing EE is not
appropriate. The pivotal registration study for E2V/CPA
was an open-label trial that recruited 288 Finnish women
aged 30–49 (mean 39.3 ± 3.4) years and was conducted
over thirteen 28-day cycles.34
E2V/DNG is available globally and is indicated for
contraception and for the treatment of heavy menstrual
bleeding in “women without organic pathology who desire
oral contraception”. The pivotal registration studies for the
contraception indication included two open-label, noncom-
parative efficacy trials, one undertaken in Europe and the
other in the US and Canada.35,36 The European study enrolled
1,377 women aged 18–50 years and was conducted over
twenty 28-day cycles.35 The US and Canadian study enrolled
499 women aged 18–35 years, and although initially planned
for 13 cycles, was later extended to 28 cycles.36 This latter
study, although undertaken to assess contraceptive efficacy,
cycle control, and safety of E2V/DNG, was not powered for
a separate Pearl Index calculation. The pivotal registration
studies for the treatment of heavy menstrual bleeding indica-
tion included two similarly designed, randomized placebo-
controlled studies, one undertaken in Europe and Australia
(n=231) and the other in the US and Canada (n=190).37,38
E2/NOMAC is available in Europe, Australia, and some
South American countries, and is indicated for contraception.
There were two pivotal registration studies for E2/NOMAC,
one conducted in Europe, Asia, and Australia30 and the
other in the US.39 Both studies were randomized open-label,
comparative trials that recruited women aged 18–50 years,
of whom 3,323 were randomized to receive E2/NOMAC and
1,110 to EE/DRSP (30 μg/3 mg; Yasmin®, Bayer HealthCare
Pharmaceuticals) for 13 cycles.
Clinical proles
Pharmacodynamic effects
The pharmacodynamic effects of E2V/CPA, E2V/DNG, and
E2/NOMAC, as well as the individual progestin components
(CPA, DNG, and NOMAC, respectively), have been well docu-
mented.26,34,40–43 In essence, the main contraceptive effects of
these combined formulations are due to the progestin compo-
nent; this is also the case with other COCs containing EE.44
CPA 1 mg daily appears sufficient to inhibit ovulation.43
A dose-ranging study of CPA (0.125–1.00 mg daily) in
healthy women aged 20–28 years (n=12) showed that CPA
1 mg inhibited ovulation (as determined by daily measure-
ments of luteinizing hormone, follicle-stimulating hor-
mone, E2, and progesterone) in all women assessed (n=5).43
Concomitant effects of CPA on the endometrium and cervical
mucus were not reported in this study.
The ovulation-inhibiting effects of DNG were assessed
in a dose-ranging (0.5 mg–3 mg DNG daily) study in healthy
women aged 18–35 years (n=102) using the Hoogland score,
which determines ovarian activity based on largest follicular
size and highest serum hormone levels.42 Dose-dependent
ovulation-inhibiting effects were observed across the doses
tested. Ovulation was suppressed in all women taking 2 mg
(n=20) or 3 mg (n=23) of DNG daily. In addition, endome-
trial thickness was reduced compared with pretreatment.
DNG also induced moderate suppression of endogenous E2
production.
The contraceptive effects of NOMAC have also been
assessed in a dose-ranging (1.25–5 mg NOMAC daily) study
in 13 healthy women. In this study, pituitary-ovarian func-
tion was determined by measuring E2, follicle-stimulating
hormone, and luteinizing hormone levels.45 Ovulation was
inhibited in all women across the doses of NOMAC. In a sepa-
rate study of 16 normally cycling women assessing the effects
of NOMAC (2.5 mg or 5 mg daily) on mid-cycle cervical
mucus, the changes observed were similar to those induced
by progesterone during the luteal phase.46 In a more recent
study, 2.5 mg of NOMAC was again shown to inhibit ovu-
lation and decrease cervical mucus scores (ie, indicative of
increased hostility to sperm penetration) in healthy women
aged 18–35 years (n=9).40 These data support cervical mucus
inhibition as a secondary contraceptive mechanism.
The approved formulations of E2V/CPA, E2V/DNG,
and E2/NOMAC all consistently inhibit ovulation in $95%
of women.26,34,40,41,47 However, studies with E2V/CPA were
performed in small samples of women with a mean age of 39
(range 30–49) years, and as such may overestimate the rate
of ovulation inhibition in “more fertile” younger women.34,41
In addition, the contraceptive effects of E2V/CPA achieved
through alteration in cervical mucus and the endometrium
have not, to our knowledge, been reported. E2V/DNG has
been shown to have suppressive effects on endometrial
growth and cervical mucus as assessed by transvaginal ultra-
sound in healthy women aged 18–35 years (n=100); mean
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Estradiol-containing oral contraceptives
maximal endometrial thickness decreased from 10.1 mm at
baseline to 6.5 mm during cycle 3. Although treatment was
associated with a reduction in the ultrasound appearance of
cervical mucus, the quality of mucus was not assessed.48
Similar changes in cervical mucus and the endometrium
were observed with E2/NOMAC in healthy women aged
18–35 years (n=32); mean maximum endometrial thickness
was reduced from 9.9 mm at screening to 4.9 mm in cycle 6.
In this study, cervical mucus, assessed using the Insler cervi-
cal mucus score, decreased from a mean maximum of 8.9 at
screening to 2.3 during the first treatment cycle (with lower
scores indicating poor likelihood of sperm penetration).47
Contraceptive efcacy
The approved E2V/CPA, E2V/DNG, and E2/NOMAC for-
mulations appear to have similar contraceptive efficacy
profiles (Table 1).30,34–36,39 The net pregnancy rate with E2V/
CPA was reported to be 0.4% over 12 months in Finnish
women (n=288) aged 30–49 years; one pregnancy occurred
in 2,800 cycles of exposure, equating to a Pearl Index of
0.46.34 Again this may be an overestimation of the contracep-
tive efficacy of E2V/CPA in younger more fertile women.
In addition, this lone study would be insufficient to meet
current recommendations for regulatory approval of a new
hormonal contraceptive in Europe (“for any new contracep-
tive, at least 400 women should have completed one year
of treatment”).49
The contraceptive efficacy of E2V/DNG was established
in two open-label, noncomparative studies, one conducted in
Europe and the other in North America, in over 1,850 women
aged 18–50 years.35,36 In the European study (conducted in
Austria, Germany, and Spain), the Pearl Index at 20 cycles of
treatment was reported to be 0.73 in women aged 18–50 years
and 0.94 in women aged 18–35 years (n=998).35 The second
study conducted in North America recruited women aged
18–35 years (n=490) and reported a Pearl Index of 1.64 at
one year; however, this study was not sufficiently powered
for a stand-alone contraceptive efficacy calculation.
The contraceptive efficacy of E2/NOMAC was estab-
lished in two randomized, open-label, comparative stud-
ies (compared with EE 30 µg/DRSP 3 mg [Yasmin]), one
conducted in Europe, Asia, and Australia,30 and the other in
the US, Canada, Argentina, Brazil, Chile, and Mexico,39 in
over 3,250 women aged 18–50 years. The study conducted
in Europe, Asia, and Australia reported a Pearl Index of
0.31 in women aged 18–50 years, and a Pearl Index of 0.38 in
women aged 18–35 years (n=1,315). The other E2/NOMAC
efficacy study reported a Pearl Index at one year of 1.13 in
women aged 18–50 years, with a corresponding Pearl Index
of 1.27 in women aged 18–35 years (n=1,375).
Of note, the Pearl indices reported at one year from the
E2V/DNG and E2/NOMAC studies that included study cen-
ters in the US were slightly higher than for the similar studies
conducted elsewhere. This is a well recognized phenomenon
in contraceptive research, and may, in part, be due to dif-
ferences in compliance rates and/or recruitment practices.50
Indeed, residential poverty level, an indirect measure of
individual income, was shown to be the strongest predictor
of noncompliance in a US oral contraceptive clinical trial.51
Nonetheless, the one-year Pearl indices for the approved
E2-containing oral contraceptives are consistent with those
reported for recently approved low-dose EE-containing
formulations (Pearl indices 0–1.6).50
Bleeding prole
A direct comparison of bleeding profile between oral contra-
ceptive formulations, especially by cycle, is difficult due to
the lack of uniform definitions and results across studies.52
Table 1 Summary of published studies reporting contraceptive efcacy of estradiol-containing oral contraceptives
Formulation Study location Treatment
duration
Age group,
years
n Exposure Pregnancies (n) Pearl
Index
Upper
95% CI
E2V/CPA34 Finland 1 year 30–49 288 2,800 cycles 1 0.46
E2V/DNG35 Austria,
Germany,
Spain
20 cycles 18–50 1,377 23,368 cycles 13 0.73 1.24
18–35 998 16,608 cycles 12 0.94 1.65
.35–50 379 6,760 cycles 1 0.19
E2V/DNG36 US, Canada 1 year 18–35 490 3,969 cycles 5 1.64 3.82
E2/NOMAC30 Europe, Asia,
Australia
1 year 18–50 1,587 1,293 woman-years 4 0.31 0.79
18–35 1,315 1,058 woman-years 4 0.38 0.97
.35–50 272 235 woman-years 0 0
E2/NOMAC39 US, Canada,
Argentina, Brazil,
Chile, Mexico
1 year 18–50 1,634 1,146 woman-years 13 1.13 1.94
18–35 1,375 946 woman-years 12 1.27 2.22
.35–50 259 235 woman-years 1 0.43
Abbreviations: CI, condence interval; CPA, cyproterone acetate; E2V, estradiol valerate; DNG, dienogest; NOMAC, nomegestrol acetate; E2, estradiol.
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Jensen et al
Although the World Health Organization has made recom-
mendations for the analysis of menstrual patterns, these have
not been uniformly adopted. Nonetheless, irrespective of defi-
nitions used, studies that assessed bleeding profiles associated
with E2V/CPA, E2V/DNG, and E2/NOMAC consistently
suggest that these oral contraceptives are associated with
shorter, lighter bleeding versus comparator EE-containing
pills or baseline.27,30,34,36,39,41
Table 2 summarizes the number of uterine bleeding days
using 90-day and 91-day reference periods observed in the
randomized controlled trials with E2V/DNG and E2/NOMAC
compared with EE/levonorgestrel (EE 20 µg/LNG 100 µg,
Miranova®, Bayer HealthCare Pharmaceuticals) and EE/
DRSP (Yasmin), respectively.27,30,39 The study with E2V/
DNG and EE/LNG was conducted over seven 28-day
cycles in centers across Germany, the Czech Republic, and
France, and reported uterine bleeding data from 399 women
aged 18–50 years in both treatment groups.27 These stud-
ies demonstrated statistically significant and/or clinically
meaningful reductions in bleeding/spotting days with E2V/
DNG and E2/NOMAC compared with the comparator
EE-based oral contraceptives.27,30,39 There are no available
bleeding data with E2V/CPA where the data are reported by
reference period.
The data reported by cycle with both E2V/DNG and
E2/NOMAC are also consistent with reduced bleeding (or
an absence of bleeding) relative to the comparator EE-
based formulations. For example, the rate of absence of
withdrawal bleeding (mean over cycles 1–7) was 19.4%
(range 16.8%–22.3%) in women treated with E2V/DNG
compared with 7.7% (range 6.2%–10.5%) in women
treated with EE/LNG.27 In the open-label North American
E2V/DNG study, the rate of absent withdrawal bleeding
occurred in a mean 23.5% of women through cycles 1–12
(range 17% and 32%).36 For E2/NOMAC, in the study
conducted in Europe, Asia, and Australia, 30% of women
had at least one absence of withdrawal bleeding during
cycles 2–4. Moreover, a progressive increase in the inci-
dence of absent withdrawal bleeding from 22% to 31%
occurred in cycles 4–12, indicating a tendency towards
absent withdrawal bleeding with continued use.30 In the
comparator EE/DRSP formulation group, the incidence of
absent withdrawal bleeding was relatively stable, ranging
from 3% to 6%. A similar trend towards absent withdrawal
bleeding with continued use (approximately 18%–34%)
was also observed with E2/NOMAC, but not with EE/DRSP
(approximately 4%–9%), in the study conducted in North
and South America.39
Table 2 Number of bleeding/spotting days associated with E2V/DNG and E2/NOMAC in randomized comparator studies (data displayed as means)
Study Ahrendt et al27,† Mansour et al30,#,‡ Westhoff et al39,‡
Formulation E2V/DNG EE/LNG E2/NOMAC EE/DRSP E2/NOMAC EE/DRSP
Reference period R1 R2 R3 R4 R1 R2 R3 R4 R1 R2 R3 R4 R1 R2 R3 R4 R1 R2 R3 R4 R1 R2 R3 R4
Bleeding/spotting days (n) 17.3* 13.4* – – 21.5 15.9 – – 15.0 12.5 11.0 10.5 18.5 16.5 16.0 19.5 14.8* – – 9.5* 17.7 – – 19.3
Spotting days (n) – – – – – – – – 9.0 8.0 7 6.5 8.0 7.0 6.5 7.0 8.9 – – 5.4 7.9 – – 7.7
Notes: #Data estimated from published graphs; ‡91-day reference period used; *P,0.001 versus comparator; †90-day reference period used.
Abbreviations: E2V, estradiol valerate; DNG, dienogest; NOMAC, nomegestrol acetate; DRSP, drospirenone; LNG, levonorgestrel; EE, ethinylestradiol.
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Estradiol-containing oral contraceptives
Intracyclic bleeding was reported to occur in approxi-
mately 14% of women receiving E2V/DNG (ranging from
10.5% to 18.6%) over cycles 1–7 compared with approxi-
mately 12% of women receiving the comparator EE/LNG
formulation (ranging from 9.9% to17.1%).27 In the open-
label, North American E2V/DNG study, intracyclic bleeding
ranged from 28.8% to 11.2% during cycles 2–13, with the
data generally indicative of a tendency to less intracyclic
bleeding with continued use.36 For E2/NOMAC, in the study
conducted in Europe, Asia, and Australia, intracyclic bleeding
progressively decreased with continued E2/NOMAC use
from about 34% to 14% (through cycles 1–13); a similar
trend was observed with the comparator EE/DRSP (28%
to 13% through cycles 1–13).30 A similar trend towards
progressively decreased intracyclic bleeding with continued
E2/NOMAC use (from about 31% to 16% through cycles
1–13) was also observed in the study conducted in North
and South America.39
The overall bleeding profile associated with E2V/CPA is
less well characterized compared with the other two approved
E2-based formulations. In the pivotal, open-label, noncompar-
ative study in Finnish women, intracyclic bleeding occurred
in 33% of E2V/CPA users (mainly spotting) at 3 months,
decreasing to 22% at 6 months and 24% at 12 months.34
Much lower rates of intracyclic bleeding were reported with
E2V/CPA (n=26) in a second study (0%–15%),which was
a randomized double-blind trial including biphasic E2V/
norethisterone, but it is not clear from the report whether
the incidence of spotting (20%–40%) included intracyclic
bleeding.41 Using the comparator E2V/norethisterone (n=24),
intracyclic bleeding occurred in 6%–42% of women (highest
during the second cycle). Absent bleeding with E2V/CPA
ranged between 5% and 19% (versus 6%–25% in the com-
parator group). The mean number of bleeding/spotting days
per cycle decreased from 5.0 ± 1 days in the pretreatment
cycle to 3.8 ± 3.3 days by cycle 12. In contrast, the number
of bleeding/spotting days per cycle remained relatively
stable with the comparator E2V/norethisterone (between
4.9 ± 1.2 days to 5.2 ± 2.5 days).
Hemostasis, lipid, and carbohydrate
metabolism, and other parameters
Generally, E2 and E2V at equimolar doses are expected to have
similar influences on hemostasis, lipids, and carbohydrate
metabolism parameters, but less than those observed with
EE. However, surrogate indices of hemostasis, lipids, and
carbohydrate metabolism, or any other surrogate marker,
cannot be translated into meaningful clinical outcomes,
and the risk of cardiovascular events in users of oral con-
traceptives containing E2 or E2V needs to be established in
large-scale, post-marketing, prospective, Phase IV cohort
studies. Indeed, two large international active surveillance
studies, ie, the International Active Surveillance Study-Safety
of Contraceptives: Role of Estrogens (INAS SCORE)53
and the Choice of estrogen and long-term investigation of
nomegestrol acetate–International Active Surveillance Study
(INAS-CELINA)54 are currently underway to investigate the
occurrence of adverse cardiovascular events within a 5-year
period in COC users (including E2V/DNG and E2/NOMAC,
respectively). To the best of our knowledge, no such active
surveillance studies have been undertaken or are planned for
the E2V/CPA oral contraceptive.
Large prospective cohort studies have the best ability to
assess uncommon adverse outcomes like venous thrombo-
sis, because their design allows for collection of baseline
information on important confounders, such as obesity and
age.55–57 Recently published database studies have suggested
that oral contraceptives containing CPA, desogestrel, or
DRSP in combination with EE are associated with an elevated
risk of venous thrombosis compared with LNG pills.58,59
However, a large prospective Phase IV study similar in
design to the INAS-CELINA and INAS-SCORE studies did
not demonstrate an increase in risk for deep vein thrombosis
with these progestins.60
E2V/CPA appears to have minimal influence on hemo-
static parameters over three cycles.41 Both total cholesterol
and high-density lipoprotein cholesterol were reported to
decrease (by 9% and 5%, respectively) relative to baseline
over 13 cycles in one study,41 but no significant changes
were reported in total cholesterol or high-density lipoprotein
cholesterol in the pivotal Finnish study.34 In the latter study,
serum triglyceride levels increased .20% over 13 cycles.34
The impact of E2V/DNG and E2/NOMAC on hemostatic
and lipid parameters relative to EE-based oral contraceptive
comparators is summarized in Table 3; both formulations
appear to have less influence on these parameters than the
EE-based formulations.61–64 However, it is important to keep
in mind that none of these potential surrogate markers of
venous thromboembolism risk have ever been validated.
Estrogens influence both thrombotic and fibrinolytic path-
ways, and the net effect on hemostasis is difficult to predict.65
High-density lipoprotein cholesterol and low-density lipo-
protein cholesterol were reported to increase and decrease,
respectively, with both E2V/DNG and E2/NOMAC during
up to seven cycles of treatment. The overall changes relative
to baseline in these parameters were ,10% for E2V/DNG
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46
Jensen et al
and ,2% for E2/NOMAC.61,63 Total cholesterol increased
with both E2V/DNG and E2/NOMAC, but by #5% rela-
tive to baseline. Mean increases in endogenous thrombin
potential-based activated protein C sensitivity ratios from
baseline to cycle 3 were significantly lower with E2V/DNG
(0.09 versus 0.56, P,0.001) and E2/NOMAC (0.20 versus
0.46, P,0.01) than with EE/LNG (EE 30 µg/LNG
150 µg; Microgynon®, Bayer HealthCare Pharmaceuticals)
or EE/LNG (EE 20 µg/LNG 100 µg; Miranova) comparators,
respectively.62,64 Additionally, insulin and glucose remained
relatively unaffected by E2V/DNG and E2/NOMAC during
oral glucose tolerance tests.61,63
The available data across four separate randomized tri-
als seem to suggest that increases in sex hormone binding
globulin (SHBG) with both E2V/DNG and E2/NOMAC are
more or less in the same range;61–64 however, increases in
SHBG with the EE-based comparators in these studies were
more inconsistent. In general, it would be expected that EE
increases SHBG levels to a greater extent than E2.
10 In COCs,
the extent of an EE-induced (or E2-induced) SHBG increase
may be attenuated by inclusion of a progestin with androgenic
activity.10 Of note, the progestins used in the three approved
E2-containing oral contraceptives do not have any androgenic
activity,66 and as such are not expected to attenuate the limited
estrogen-induced SHBG increase with the E2-containing oral
contraceptives.
Safety and tolerability
The relevance of nonspecific adverse events with oral contra-
ceptives reported outside randomized placebo-controlled trials
has been questioned because the limited level I evidence sug-
gests that these nonspecific events may not occur significantly
more often with oral contraceptives and that they may simply
reflect their background prevalence in the population.67 With
this in mind, the adverse events reported in the E2V/CPA, E2V/
DNG, or E2/NOMAC studies with .250 patients receiving
one of the three oral contraceptives that were judged to be
treatment-related were in general typical of those reported
with EE-based oral contraceptives.27,30,35,36,39 Results from
the randomized comparator studies of E2V/DNG and E2/
NOMAC show a similar distribution of adverse events. In the
only placebo-controlled studies, where E2V/DNG was used to
manage heavy menstrual bleeding in North America and in
Europe/Australia, breast pain and irregular bleeding were more
common in women receiving E2V/DNG, while headache was
more commonly reported with placebo (Table 4).37,38 For E2V/
CPA (n=288) in the Finnish study, adverse events reported after
6 months included breast tenderness (9.4%), edema (8.5%),
Table 3 Changes from baseline in hemostatic, lipid, and carbohydrate metabolism indices
Junge et al61,#
(7 cycles)
Klipping et al62,#
(3 cycles)
Agren et al63
(6 cycles)
Gaussem et al64
(3 cycles)
Formulation E2V/DNG EE/LNG E2V/DNG EE/LNG E2/NOMAC EE/LNG E2/NOMAC EE/LNG
Hemostasis
Prothrombin
fragment 1 + 2
= +++ = ++ = + = +
D-dimer = +++ ++ +++ = = - - +
Fibrinogen = ++ + ++ NR NR = +
Factor VII activity + ++ = = =Φ+ΦNR NR
Factor VIII activity = = = = = = = =
Antithrombin III
activity
= = = = = = = =
Protein C activity = + = = =‡=‡NR NR
APC sensitivity
ratio (aPTT)
= = = = = = NR NR
APC sensitivity ratio NR NR =¥++¥+++ +++ ++¥++¥
PAI-1 antigen - - -NR NR NR NR - - - - -
PAI-1 activity = = NR NR NR NR NR NR
Lipid
Total cholesterol = = NR NR = = NR NR
High-density lipoprotein = = NR NR = - NR NR
Low-density lipoprotein = = NR NR = = NR NR
Triglycerides ++ ++ NR NR = + NR NR
Notes: #Intraindividual change; ¥nAPC-r, Rosing’s activated protein C resistance normalized ratio; Φfactor V11a or VIIc; =, no change (,10% change); +, $10% increase;
-, $10% decrease; ++, $20% increase; - -, $20% decrease; +++, $50% increase; - - -, $50% decrease.
Abbreviations: APC, activated protein C; aPTT, activated partial thromboplastin time; NR, not reported; PAI-1, plasminogen activator inhibitor type 1; E2V, estradiol
valerate; DNG, dienogest; NOMAC, nomegestrol acetate; EE, ethinylestradiol; LNG, levonorgestrel.
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47
Estradiol-containing oral contraceptives
headache (6.6%), and depression (4.2%), decreasing to 7.7%,
5.5%, 4.4%, and 2.7%, respectively, by 12 months.34
Discontinuations due to adverse events during up to 20 cycles
of treatment with E2V/DNG were reported to be up to 14%,27,35,36
with discontinuations due to bleeding problems ranging up to
5% over the first year of use.36 Similar discontinuation rates were
documented for E2/NOMAC, with up to 18% discontinuing due
to adverse events over one year and up to 5% due to bleeding
problems.30,39 For E2V/CPA, 16% of women discontinued due to
adverse events typically related to hormone use (“edema, breast
tenderness, headache, weight change, and mood changes”) over
one year and 9% due to menstrual problems.34
The effects of E2/NOMAC (n=56) on bone mineral den-
sity were compared with those of EE/LNG (EE 30 µg/LNG
150 µg; Microgynon, n=54) in women aged 20–35 years
over 2 years in a randomized controlled trial.68 No clinically
relevant effects on bone mineral density were observed during
this time with E2/NOMAC or with the EE/LNG oral contra-
ceptive comparator. In the absence of data on the effects of
E2V/DNG or E2VCPA on bone mineral density, it might be
postulated that because similar doses of E2 are used relative to
E2/NOMAC, the effects on bone density would be similar.
Other indications and benets
The choice between the E2V/CPA, E2V/DNG, and E2/NOMAC
formulations is currently restricted by regional availability;
so far, only Finnish women have access to all three E2-based
formulations. Elsewhere, women have either the option of
E2V/DNG or E2/NOMAC (eg, Europe) or E2V/DNG (eg, the
US) alone as the only available E2-based formulations.
Several studies have been conducted with E2V/DNG
to assess additional health benefits. No studies assessing
additional health benefits associated with the other two
E2-based formulations have been published. E2V/DNG has
been shown to profoundly reduce menstrual blood loss in
women with objectively confirmed heavy menstrual bleed-
ing without organic pathology in two randomized, placebo-
controlled, double-blind studies, one conducted in the US
and Canada and the other in Europe and Australia.37,38 These
studies led to the approval of E2V/DNG for the treatment
of heavy menstrual bleeding, a unique indication for this
oral contraceptive formulation. The effect is rapid, with
the greatest reduction in menstrual blood loss achieved
by the first withdrawal bleed after treatment initiation and
maintained with no loss of effect with continued treatment.
Moreover, the observed reduction in menstrual blood loss
with E2V/DNG (median 88% reduction after seven cycles
of treatment) appears to approach that achieved with the
LNG-releasing intrauterine system.69 Overall, 64% of
women with excessive menstrual blood loss receiving E2V/
DNG met the study criteria for treatment success (defined as
menstrual blood loss ,80 mL and a $50% reduction from
baseline) compared with only 12% with placebo.70 Second-
ary endpoints in the two randomized studies included the
impact of treatment with E2V/DNG on heavy menstrual
bleeding-related impairment of work productivity (pre-
senteeism) and activities of daily living.71,72 These studies
showed that E2V/DNG had a consistent positive impact on
work productivity and activities of daily living in women
with heavy menstrual bleeding, and that these improvements
could be translated into a reduction in the monetary burden
associated with this condition.
Two more randomized, double-blind, active-controlled
studies, one conducted in North America and the other in
Western Europe, Thailand, Australia, and Mexico, were
undertaken to assess the effect of E2V/DNG on hormone
withdrawal-associated symptoms (principally headache or
pelvic pain) in women (n=414, across both studies) who
experienced these symptoms with other COCs taken in the
traditional 21/7 regimen.73,74 Switching to E2V/DNG was
shown to reduce the severity of these symptoms to a greater
extent than switching to comparator triphasic EE/norgesti-
mate (Ortho Tri-Cyclen® Lo, Ortho-McNeil-Janssen Phar-
maceuticals Inc, Raritan, NJ, USA; n=204) or a monophasic
EE/LNG (Microgynon; n=218).
Table 4 Common adverse events (in alphabetical order) in
subjects treated with estradiol valerate/dienogest or placebo in
two randomized trials
Adverse events, n (%) E2V/DNG (n=264) Placebo (n=147)
Subject-reported events
Acne 11 (4.2) 3 (2.0)
Back pain 6 (2.3) 7 (4.8)
Breast pain 13 (4.9) 0 (0.0)
Breast tenderness 10 (3.8) 4 (3.7)
Headache 26 (9.8) 21 (14.2)
Metrorrhagia 14 (5.3) 1 (0.7)
Nasopharyngitis 21 (8.0) 4 (6.8)
Nausea 13 (4.9) 7 (4.7)
Vomiting 5 (1.9) 6 (4.1)
Notes: Adapted with permission from Fraser IS, Römer T, Parke S, et al. Effective
treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive
containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial.
Hum Reprod. 2011;26:2698–2708.37 Adapted with permission from Lippincott Williams
& Wilkins/Wolters Kluwer Health: Obstet Gynecol. Jensen JT, Parke S, Mellinger U,
Machlitt A, Fraser IS. Effective treatment of heavy menstrual bleeding with estradiol
valerate and dienogest: a randomized controlled trial. 2011;117:777–787.38
Copyright © 2011. Promotional and commercial use of the material in print, digital
or mobile device format is prohibited without the permission from the publisher
Lippincott Williams & Wilkins. Please contact journalpermissions@lww.com for further
information.
Abbreviations: E2V, estradiol valerate; DNG, dienogest.
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Jensen et al
A multicenter, double-blind, randomized study was
conducted in Europe and Asia/Pacif ic to determine the
effect of E2V/DNG (n=92) on oral contraceptive-related
sexual dysfunction using EE/LNG (Microgynon, n=99) as
a comparator.75 Among women reporting baseline sexual
dysfunction while using an oral contraceptive, switching to
either E2V/DNG or EE/LNG resulted in similar improve-
ments in desire and arousal, a reduction in associated distress,
and decreased vaginal symptoms. A study from Italy also
suggested some benefit on sexual function with E2V/DNG
(n=57), but the open-label noncomparative nature of this
study provides no reference for the observed changes, making
it impossible to draw conclusions from these results.76
Conclusion
In summary, E2V/DNG, E2/NOMAC, and E2V/CPA are all
effective oral contraceptives. The contraceptive effectiveness
of E2V/CPA was, however, assessed in women with a mean
age of 39 years, and as such may not be directly generalizable
to younger more fertile women. Although direct comparability
between the studies is difficult, the available data suggest that
E2V/DNG and E2/NOMAC may have better bleeding profiles
than E2V/CPA. Currently, E2V/DNG is the only oral contracep-
tive approved for the treatment of heavy menstrual bleeding.
Emerging data suggest that E2V/DNG may be a good alterna-
tive to other COCs taken in the conventional 21/7 regimen for
women susceptible to hormone-associated withdrawal symp-
toms, but there is insufficient evidence to conclude whether
the effect is due to the components of the formulation or the
dosing regimen. Both E2V/DNG and E2/NOMAC generally
have minimal influence on hemostatic, lipid, and carbohy-
drate metabolism parameters, or induce less change in these
parameters than EE-based oral contraceptives. Whether these
differences can translate into meaningful clinically important
outcomes (specifically cardiovascular events) needs to be
established in future large-scale prospective studies.
Disclosure
Jeffrey T Jensen has received payments for consulting
and giving talks for Bayer HealthCare Pharmaceuticals,
a company that may have a commercial interest in the results
of this research and technology. This potential conflict of
interest has been reviewed and managed by Oregon Health
and Science University. Jeffrey T Jensen is also a consul-
tant and speaker for Merck Sharp & Dohme, a consultant
for HRA Pharma and Agile Pharmaceuticals, and has
received research funding from Abbott Pharmaceuticals,
Bayer HealthCare, Warner Chilcott, the Population Council,
and the National Institutes of Health. Johannes Bitzer
has participated in advisory boards for Bayer HealthCare
Pharmaceuticals, Merck Sharp & Dohme, Lilly, Solvay
Pharma, and Boehringer Ingelheim, and has lectured at
meetings supported by Bayer HealthCare Pharmaceuti-
cals, Merck Sharp & Dohme, Lilly, Solvay Pharma, and
Boehringer Ingelheim. Marco Serrani is an employee of
Bayer HealthCare Pharmaceuticals, the manufacturer
of E2V/DNG. Richard Glover and Latoya M Mitchell of
inScience Communications, Springer Healthcare, provided
writing assistance during development of this manu-
script. This assistance was funded by Bayer HealthCare
Pharmaceuticals.
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