Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: https://www.tandfonline.com/loi/igye20

Analysis and new contraception frontiers with

combined vaginal rings

Patricio Barriga Pooley, Andrea Von Hoveling, Guillermo Galán & Jorge López
Berroa

To cite this article: Patricio Barriga Pooley, Andrea Von Hoveling, Guillermo Galán & Jorge López
Berroa (2020): Analysis and new contraception frontiers with combined vaginal rings, Gynecological
Endocrinology, DOI: 10.1080/09513590.2020.1729730

To link to this article: https://doi.org/10.1080/09513590.2020.1729730

Published online: 24 Feb 2020.

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GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2020.1729730

REVIEW

Analysis and new contraception frontiers with combined vaginal rings

Patricio Barriga Pooleya, Andrea Von Hovelingb, Guillermo Gal
anc and Jorge Lo

pez Berroad
a
Women’s Healthcare Service (Obstetrics and Gynecology Department), School of Medicine Finis Terrae and San Sebastian Universities,
Santiago, Chile; bCl
ınica Santa Mar
ıa y Hospital El Carmen de Maip
u, Santiago, Chile; cCentro de Capacitaci
on e Investigaciones Cl
ınicas,
Santiago, Chile; dLATAM Exeltis, Panama City, Panama

ABSTRACT ARTICLE HISTORY

Combined vaginal rings (ethinylestradiol (EE)/desogestrel), indicated for contraception, are highly effective, Received 30 September 2019
comparable to other combined hormonal contraceptives, such as pills. In addition to this benefit, vaginal Revised 21 January 2020
rings are easy to use, with a probable lower risk of forgetting, due to their non-daily, monthly schedule. Accepted 11 February 2020
Besides, for users with poor gastric tolerance to oral formulations, they represent a method with safety Published online 21 February
2020
and comparable extraconceptive benefits. The latest generation rings have a novel polymeric structure,
do not need special storage methods and do not generate accelerated initial release of EE, reducing the KEYWORDS
early increased systemic exposure to the synthetic steroids they contain. This review describes main Vaginal ring; contraception;
aspects related to its use, efficacy, and safety for contraceptive purposes. polymers; Latin America

Introduction patient-reported advantages were its monthly use (73% of users),

Vaginal rings are a proven and interesting alternative of adminis-
tration of a combined hormonal contraceptive method [1]. The
advantages of this administration route include a constant and
steadily over-time hormonal release, as well as minimizing the
hepatic first pass metabolic impact when compared to the com-
bined oral contraceptives (COCs) [1]. As a direct consequence of
the steroids vaginal release, favorable effects are obtained, such
as the control of the cyclic bleeding pattern, which makes it pos-
sible to use lower systemic doses of ethinylestradiol (EE) and
potentially decrease the probability of occurrence of some estro-
gen-dependent adverse effects [1]. Over the years, different types
of vaginal rings have been evaluated in terms of their structure,
size, polymers used in their composition and hormonal deriva-
tives they contain [1]. Current formulations contain etonogestrel
and EE, as discussed in the following section [1].
The pharmacokinetic characteristics of the combined contra-
ceptive vaginal rings (CVRs), as well as their high levels of effi-
cacy and safety, have been published in several recognized
scientific journals [2]. As demonstrated in a randomized trial,
exposure to EE was significantly reduced with a vaginal ring
releasing 15 mg/day than with a transdermal patch (EE 20 mg/
day) or a COC containing 30 mg of EE (3.4 times and 2.1 times
lower, respectively) [3]. CVRs containing etonogestrel and EE
are associated with minimal impact on hemostatic variables, as
reported with COCs [4].
It has been shown that a correct counseling on using self-
administrated hormonal contraceptive methods improves the
choice of CVRs in Latin American population [5,6]. A regional
Latin American study showed that counseling by healthcare pro-
fessionals is linked to a 15–33% increase in the choice of CVRs
and to a reduction in the pills use from 57% to 38%, due to the
comfort and ease of use [6]. In another study with 867 users
who opted for a CVR containing etonogestrel and EE, main
a lower probability of forgetting (66%), and ease of use
(65%) [5].
Mechanism of action
Contraceptive action of the combination of estrogens and pro-
gestagens are linked to ovulation inhibition and alteration of cer-
vical mucus permeability [7,8]. The progestagen contained in
CVRs is etonogestrel, the active metabolite of desogestrel, which
is released from the polymer ring and effectively absorbed
through the vaginal mucosa. This allows the progressive increase
in plasma concentrations during the first week and the subse-
quent reaching of maximum levels, which finally decrease when
the optimum recommended use period is reached. On the other
hand, EE reaches its maximum plasma concentrations around
48–72 h after the placement of the CVR, with a gradual decrease
in the following days [9]. As a final result, systemic exposure to
etonogestrel is similar for CVRs and COCs, but exposure to EE
is reduced by 50% with the vaginal administration [9]. Mean eto-
nogestrel plasmatic concentrations were above the threshold lev-
els which effectively prevents ovulation [10].
In a randomized, crossover study, effects on ovulation inhib-
ition of a CVR releasing etonogestrel and EE was compared with
a COC containing EE and desogestrel (150 mg). During a period
of 3 weeks, the CVR was associated with a complete ovulation
inhibition assessed by ovarian follicular diameter and serum lev-
els of gonadotropins. Inhibition of ovulation was maintained for
an additional 2 weeks period of CVR use. Ovarian suppression
was comparable for both contraception methods [11].
A new type of CVR (ExelringV, Exeltis, Santiago, Chile) is
R
available, with differences in the composition of the polymers,
where the core is made of polyurethane and an outer membrane
also with a polymer composed of vinyl acetate and 28% of

CONTACT Patricio Barriga Pooley dr.patriciobarriga@gmail.com Women’s Healthcare Service (Obstetrics and Gynecology Department), School of Medicine Finis
Terrae and San Sebastian Universities, Santiago, Chile
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 P. BARRIGA POOLEY ET AL.
Figure 1. Incidence of unexpected bleeding in users of vaginal rings and COC. COC: combined oral contraceptives (ethinylestradiol 30 mg þ levonorgestrel 150 mg).
p<.003. Adapted and modified from Oddsson et al. [24].
ethylene [2]. Although it has no major difference with respect to
the first CVR in terms of the average daily release of etonogestrel
and EE, this structural modification allows a greater stability of
the device and a more gradual release of the active ingredients
during the first day of use [2]. It is worth to mention that, given
the new polymer composition, this CVR does not require any
special storage temperature [12], unlike the first formulation that
requires cold chain maintenance for transport and storage until
it is delivered to the end user.
In addition, CVRs do not lead to unfavorable changes in the
usual vaginal flora (microbiota) over time, even in subgroups
that have a high baseline prevalence of bacterial vaginosis [13].
The polymer structure of the new CVR, such as ExelringV, is
R
characterized by a softer surface, which would induce favorable
modifications in the local microenvironment, preventing further
proliferation of C. albicans [14]. Even though favorable data
from an in vitro trial are available [14], potential clinical benefits
need to be demonstrated in future research.
Efficacy and safety
The high efficacy of CVRs has been demonstrated in clinical
studies, which show significant differences when compared to
COCs [15]. This high efficacy is also accompanied by high rates
of continuity of use, acceptability, and therapeutic compliance
[16]. The studies on CVRs use mainly include sexually active
women aged 18 or older, who have a greater understanding of
their use, taking care of the correct counseling and compliance
with the medical eligibility criteria for combined hormonal con-
traceptives [17].
A phase III, open-label, randomized, multicenter trial, com-
pared a CVR releasing EE and etonogestrel (n ¼ 512) with a
COC containing 150 mg of levonorgestrel and 30 mg of EE
(n ¼ 518). The percentage of women in the intention-to-treat
(ITT) population who completed the trial was 70.9% for the
CVR group and 71.2% for the COC group. Five in-treatment
pregnancies occurred in each group, with respective Pearl indices
(PIs) of 1.23 and 1.19 [18].
In addition, the contraceptive efficacy of a CVR containing
EE and etonogestrel was examined in two 1-year, open-label,
non-comparative studies conducted in Western Europe
(n ¼ 1145) [19] and in North America (n ¼ 2322) [20]. PIs for
the ITT populations were 0.65 in the European study [18] and
1.75 in the American study [19]. Pooling the pregnancy rates
(n ¼ 6 and n ¼ 15, respectively) of both studies resulted in a PI
of 1.18 (95% CI ¼ 0.73–1.80) [21]. The overall cumulative preg-
nancy rate for pooled data, calculated from life table analysis,
was 1.18% (95% CI ¼ 0.68–1.69), comparable with the PI. The
pooled method-related PI was 0.77 (95% CI ¼ 0.37–1.40) [20].
In a recent Chinese phase III, open-label, randomized multi-
center trial, contraceptive efficacy of a CVR containing etonoges-
trel and EE (n ¼ 732) was compared to a COC (30 mg EE and
3 mg drospirenone; n ¼ 214). Ten in-treatment pregnancies in
the CVR group (PI 1.92; 95% CI: 0.92–3.53) and five in the
COC group (PI 3.12; 95% CI: 1.01–7.29) were reported. Absence
of withdrawal bleeding ranged from 8.6% (cycle 1) to 3.0% (cycle
11) for the CVR and from 14.6% (cycle 1) to 6.4% (cycle 5) for
COC users. Rates of treatment discontinuation for adverse events
were 7.0% and 9.1%, respectively [22]. Efficacy of CVRs is not
modified in specific population groups, such as obese patients
without exclusion criteria for the use of a combined hormonal
contraceptive [23].
Like other hormonal contraceptive methods, CVRs do not
protect against sexually transmitted infections, including the
human immunodeficiency virus. Double protection with con-
doms should be informed and recommended to users [17].
For new users who have not used hormonal contraception in
a previous cycle, it is recommended to insert the CVR on the
first day of menstruation, although it is possible to implant it
between the second and fifth day, adding a barrier method dur-
ing the first week [12]. The indication is similar if the CVR is
used on any day of the cycle (‘quick start’ modality, initiating on
the same day of the medical consultation and regardless of the
cycle day) [12]. In the absence of bleeding, it is advisable to rule
out pregnancy before starting the use of a CVR.
In women who are using another combined hormonal contra-
ceptive, the CVR is ideally placed on the first day of bleeding
and not beyond the day immediately after the usual rest period
of the previous method, if so was used [12].
In comparative models, the incidence of unexpected uterine
bleeding and spotting within a same cycle for new generation

Figure 2. Bioequivalence between CVRs. CVR: combined vaginal ring; EE: ethinylestradiol; ETO: etonogestrel. Adapted and modified from Algorta et al. [2].
CVRs ranges from 2% to 6.4% of users [12,24]. In most of these
women, bleeding occurs during the hormone-free period, with-
out using the CVR [12] (Figure 1).
In a clinical study designed to collect data on cycle-related
symptoms with a CVR releasing etonogestrel and EE (n ¼ 1053),
menstrual headache, dysmenorrhea, and premenstrual symptoms
improved both in CVR starters and among switchers from COC
[25]. In addition, in a randomized trial, a CVR (15 mg EE þ
150 mg etonogestrel) was compared to a COC containing 20 mg
EE þ 100 mg levonorgestrel, administered during 360 days on a
menstrual-signaled regimen. Both schemes were associated with
a reduction in the mean (± standard deviation) number of bleed-
ing/spotting days from a first 90-days reference period (CVR:
14.2 ± 10; COC: 16.6 ± 10.9) to a fourth 90-days reference period
(CVR: 8.8 ± 9.6; COC: 8.8 ± 9.1). Bleeding patterns with continu-
ous use of both the methods were similar and improved over
1 year of use [26].
In relation to safety, although the risk of venous thrombo-
embolism is a cause for concern in hormonal contraceptive
methods that contain an estrogen, CVRs pharmacokinetic prop-
erties are characterized by a less systemic exposure to these hor-
mones [9] and randomized clinical trials that compared CVRs
with COCs showed that this adverse event is very infrequent,
without difference between both methods [27].
Expulsion of the ring is reported by 4–20% of women and
local adverse events are the main reason for discontinuation
[28]. Local adverse event mainly includes leukorrhea (5.3%) and
vaginitis (5.0%) [29]. Except for vaginal effects, most adverse
symptoms, especially those that are estrogen-related (nausea,
breast tenderness), seem to be fewer with the CVR releasing EE
and etonogestrel, compared with COCs [27].
As previously described, both methods share the same use
restrictions, related to the cardiovascular risk, among other issues
[17].
Comparative studies between CVRs
A randomized, crossover, comparative trial evaluated the bio-
availability of steroid hormones of both CVRs [2]. Forty healthy
women used one CVR during 4 weeks and, after a same duration
washout period, were crossed over for using the other CVR.
Serial serum samples were obtained to determine the plasmatic
GYNECOLOGICAL ENDOCRINOLOGY 3
levels of EE and etonogestrel. A register of clinical adverse events
and eventual laboratory alterations was performed, as well as an
evaluation of local tolerability through a vaginal examination.
CVRs acceptability was evaluated by a Likert scale question-
naire [2].
Bioequivalence between both CVRs was demonstrated, since,
for both etonogestrel and EE, the main pharmacokinetic parame-
ters (area under the curve and maximum concentration) were
within the accepted variability range between 80% and 125%. It
was observed that the new generation CVR, unlike the traditional
ring method, was not associated with a peak of greater absorp-
tion of EE on the first day of use [2] (Figure 2).
Acceptability rates were similar for both CVRs, without inter-
fering in women’s daily lives. Besides, no discomfort during
intercourse was notified with any of the tested CVRs, tolerability
was similar for both CVRs and no signs of moderate to severe
vaginal mucosa irritation were observed during the clinical
examination [2].
Conclusions
COCs have high rates of efficacy in clinical trials; however, their
real effectiveness is reduced in daily practice in many users, due
to factors like inadequate use or interruptions [5]. It has been
demonstrated that contraceptive counseling, provided by health-
care professionals, is linked to an increasing preference for meth-
ods like CVRs [5,6], due to considering their ease to use and the
lower probability of forgetting [5]. A lower systemic exposure to
EE [9] with a safety and efficacy profiles comparable to that of
COCs [12,26] are worth mentioning.
Current sexually transmitted diseases rates in Latin America
[30], especially in subjects younger than 25 years-old, make it
mandatory to address the importance of double protection in
each consultation in which contraception is discussed.
Disclosure statement
Dr. Barriga, Dr. Gal
an, and Dr. Von Hoveling report no conflict of
interest. Dr. L

opez-Berroa is the Exeltis LATAM Medical Director.
4 P. BARRIGA POOLEY ET AL.
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