Contraception 87 (2013) 264 272

Review article

Current status of contraceptive vaginal rings

Vivian Brache a,, Luis Jos Payn a , Anbal Faundes b
a
PROFAMILIA, P.O. Box 1053, Santo Domingo, Dominican Republic 10401
b
Centro de Pesquisas en Sade Reprodutiva de Campinas, Cemicamp, 13084-970, Campinas, SP, Brazil
Received 12 July 2012; accepted 26 August 2012

Abstract

Contraceptive vaginal rings (CVR) offer a new, effective contraceptive option, expanding the available choices of hormonal
contraception. Various ring prototypes have been evaluated: progestin-only rings and combined progestin-estrogen rings, as well as different
combination of progestins and estrogens. The progestin-only ring is intended for continuous use, whereas the combined ring has been
designed for cyclic 3-week in/1-week out use, although several studies have explored alternative schemes of extended use. However, only
two ring designs have reached the market: NuvaRing, a 1-month combined ring that releases etonogestrel and ethinylestradiol, and Progering,
a 3-month progesterone-releasing ring for use in lactating women. A one year Nestorone/ethinyl estradiol CVR is approaching the final
stages of development, as the Population Council is preparing to submit a new drug application to the Food and Drug Administration. The
main advantages of CVRs are their effectiveness (similar or slightly better than the pill), ease of use without the need of remembering a daily
routine, user ability to control initiation and discontinuation, nearly constant release rate allowing for lower doses, greater bioavailability and
good cycle control with the combined ring, in comparison with oral contraceptives. Current prototypes in development include rings
releasing progesterone receptor modulators, which would provide estrogen-free contraception, as well as combined rings releasing estradiol,
instead of ethinyl-estradiol, providing a safer profile. Furthermore, intensive efforts towards developing dual protection rings, providing both
contraception and protection against reproductive tract infections, offer hope that this greatly needed technology will soon undergo clinical
testing and will be in the hands of women worldwide in the near future.
2013 Elsevier Inc. All rights reserved.

Keywords: Contraceptive vaginal rings; Hormonal contraception; Long-acting contraception; Dual protection technology; Multipurpose technologies

1. Introduction tended pregnancies decreases [2,3]. However, most LARCs,

The percentage of women worldwide who choose to use
contraceptive methods has been steadily increasing as
women have recognized the benefits that contraception has
on their sexual and reproductive health as well as on their
social and economical development. However, the unmet
need for contraception is still very high in the developing
world, with an estimated 215 million women who want to
avoid pregnancy but are not using an effective method of
contraception. Furthermore, women with this unmet need
account for 82% of all unintended pregnancies [1].
There is an increasing recognition that as the proportion
of contraceptive users who rely on long-acting reversible
contraceptives (LARC) increases, the proportion of unin-
Corresponding author. Tel.: +809 681 8357; fax: +809 536 2742.
E-mail address: vbrache@gmail.com (V. Brache).
0010-7824/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.contraception.2012.08.037
such as intrauterine devices (IUDs) and contraceptive
implants, are provider dependent, which may be an
important limitation in environments where there is scarcity
of trained providers. Contraceptive vaginal rings (CVRs) can
provide long-acting effective contraception, yet are user
controlled giving women the opportunity to initiate or
discontinue use whenever desired.
The proof of concept for the development of a
contraceptive ring was first demonstrated in the late 60s,
when Mishell and Lumkin [4] published their study with a
medroxyprogesterone acetate-releasing ring. The Interna-
tional Committee for Contraception Research of the
Population Council (New York, NY, USA) took the initial
lead in the development of the rings, conducting a large
number of trials delivering both a progestin and an estrogen,
as well as progestin-only rings for continuous use. In spite of
decades of studies, only two contraceptive rings have
become marketed products: the NuvaRing developed by
 V. Brache et al. / Contraception 87 (2013) 264272
NV Organon (Oss, the Netherlands), which releases
etonogestrel (ENG) (3-keto-desogestrel) and ethinyl estradi-
ol (EE) and the progesterone-releasing vaginal ring for
nursing women, Progering (Laboratorios Andromaco,
Santiago, Chile).
Promises of several new developments such as estrogen-
free rings and dual protection rings, which will provide
protection against sexually transmitted infections, including
HIV and HSV, as well as pregnancy, are in the near future. A
critical analysis of the past development and current status is
presented below.
2. Rationale for development of vaginal rings
The concept of CVRs is based on a combination of two
principles: the capacity of steroids to slowly diffuse at a
constant rate through bio-compatible silicone elastomers [5],
and the capability of the vaginal epithelium to rapidly absorb
steroids placed in the vagina into the circulation, making it a
very effective route of administration. [6,7]. The vaginal
route for administration of steroids or other drugs avoids
gastrointestinal absorption and hepatic first-pass metabo-
lism, and provides greater bioavailability, as compared with
the administration of the same doses of steroids by other
routes [8]. This makes it feasible to use lower doses and
lower systemic exposure, yet achieving the same pharma-
codynamic effect.
Most devices have an initial burst effect due to
accumulation of steroids on the surface of the ring during
storage [912], but after this burst, a constant drug release
from the steroid reservoir in the elastomer results in steady
blood levels of the minimum dose required, in contrast with
the daily fluctuations of steroids associated with oral
contraceptives (OC). In addition, orally inactive steroids
can be administered using a vaginal ring.
The site in the vagina where the ring is placed is irrelevant
for drug absorption, as any part of the vaginal epithelium is
equally capable of allowing the transfer of steroids into the
blood stream; however, the ring should be inserted high
enough in the vagina, so that the woman does not feel the
ring and is comfortable.
3. Progestin-only rings
Three progestin-only rings have been evaluated: the
progesterone, the levonorgestrel (LNG) and the Nestorone
(NES) releasing rings. These rings are designed for
continuous use.
3.1. Progesterone-releasing ring
The only progestin-ring currently marketed is the
progesterone-releasing (10 mg/day) vaginal ring for breast-
feeding women (Progering, Laboratorios Andromaco, San-
tiago, Chile), which has been approved for use in Chile,
265
Peru, Bolivia, Dominican Republic, Ecuador, Guatemala and
Panama under the trade name Progering.
Initial studies with the progesterone vaginal rings (PVR)
were conducted in Santiago, Chile, by Diaz et al. [13].
Progesterone (P) has potential advantages for contraception
during lactation because it is a natural hormone and is nearly
inactive when given by the oral route, thus is unlikely to
affect the infant even when present in breast milk.
Furthermore, it prolongs lactational amenorrhea which is
an additional health benefit for women with anemia, as
reduced bleeding improves hemoglobin levels [13,14]. An
extensive review of the progesterone ring was recently
published [15].
This ring prototype, with an external diameter of 58 mm.
and a cross-sectional diameter of 8.4 mm, developed by the
Population Council, is composed of a homogeneous mixture
of soft, flexible silicone elastomers and micronized P. The in
vitro release is approximately 10 mg/day of P for an effective
life span of three months. Due to its homogenous design, the
PVR has declining serum levels throughout its 3-month
duration of use. The highest P concentrations are attained at
week 1 of ring use (33.7 nmol/L), decreasing to 50% and
30% of this level at 9 and 16 weeks of use [16].
The Population Council conducted a large multicenter
trial among lactating women comparing the 10 mg/day P
ring (n=802) with the copper T 380A (n=734) [17]. The 1-
year pregnancy rate for the PVR was 1.5 per 100 and did not
differ significantly from the IUD. Ring users had more
complaints of vaginal problems than IUD users (25.8% and
16.8%, respectively). Only 5.8% of users had discontinued
for menstrual problems at 12 months, while 46 per 100
continuing ring users remained in amenorrhea at 12 months
postpartum. Lactation performance and the health and
weight gain of the infants were similar among users of
either the ring or the IUD.
Two further studies conducted in Chile confirmed the
efficacy and safety of the ring, for both mother and infant.
These results led to the registration of the PVR by the
Chilean Public Health Institute in February 1998, being the
first vaginal ring approved for contraceptive use during
lactation [14,16]. A subsequent study evaluated the extended
use of the ring up to 4 months (instead of 3) in 192 users,
concluding that it was safe and effective for contraception in
nursing women for this period of time [18].
Currently, a large study with the PVR is being conducted in
20 centers in India by the Indian Council of Medical Research
in collaboration with the Population Council. Its purpose is to
confirm the contraceptive efficacy, as well as to evaluate
safety, child development, bleeding patterns and acceptability
in different populations where breastfeeding is popular.
[Clinical trials registry in India CTRI/2011/07/001874].
3.2. Levonorgestrel rings
The Special Programme of Research, Development and
Research Training in Human Reproduction of the World
266 V. Brache et al. / Contraception 87 (2013) 264272
Health Organization (WHO) initiated development of a 3-
month LNG vaginal ring releasing 20 mcg/day in the mid
1970s. This ring prototype was tested in a WHO multicenter
clinical trial involving 1005 women accumulating 8176.4
women-years of exposure and reported a cumulative 1 year
pregnancy rate of 4.5% (confidence interval 2.9-6.0) [19].
Menstrual disturbances led to a 17.2% discontinuation rate at
1 year. Vaginal erythematous reactions located in the
posterior fornix of the vagina of some women participating
in a subsequent LNG CVR clinical trial in the UK were
reported at one center [20]. The etiology of these lesions was
unknown, although it was hypothesized that they could be
due to a combined effect of pressure from the ring and
thinning of the vaginal epithelium due to local exposure to
LNG. In addition, earlier rings were manufactured with a rim
that may have irritated the vagina, while all the following
rings are now manufactured in one mold without any rim.
3.3. Nestorone rings
The Population Council conducted a dose-finding study
with three prototypes of NES-only rings, releasing 50, 75 or
100 mcg/day of NES [9,21]. NES is a highly potent 19-nor
progesterone, with an excellent metabolic profile, which is
not orally active, but is effective when administered via non-
oral routes such as vaginal rings. All three doses were very
effective in inhibiting ovulation, however, menstrual irreg-
ularities were common, and more so in the lower doses,
while the higher dose was associated with reduced bleeding.
The low-dose NES ring was also tested successfully in a pilot
study as a contraceptive for breastfeeding women [22]. Due
to the irregular bleeding pattern, no further development of
this progestin-only ring has followed. However, higher doses
may lead to better cycle control, and ring prototypes with a
low dose of estradiol as a back-up, are currently being tested.
4. Combined rings
Combined rings have the advantage that estrogen in-
creases the contraceptive efficacy of the progestin by a
synergistic effect on ovulation inhibition, but most impor-
tantly, estrogen maintains endometrial development, pre-
vents breakthrough bleeding and thus provides good
menstrual cycle control with regular withdrawal bleeding
patterns. Combined rings have been mostly used on a 3-week
in/1-week out schedule, allowing for regular once a month
withdrawal bleeding.
4.1. LNG/E2 and norethindrone acetate (NETAc)/EE rings
The Population Council developed a combined ring
releasing levonorgestrel (250290 mcg/day) and estradiol
(150180 mcg/day) [23,24] which was tested in a large
multicenter comparative trial in the early 1980s. Clinical
performance and effectiveness was similar between ring and
combined oral contraceptive users [2527]. However,
further development of the LNG/E2 rings was halted due
to undesirable reductions in high-density lipoprotein choles-
terol [2830] and to the finding of an increase in coronary
artery atherosclerosis among cynomolgus macaques treated
with this ring prototype [31]. Both findings may be attributed
to the androgenic effect of LNG not counterbalanced by a
weak estrogen. Several smaller Phase II studies evaluating
different dose combinations of norethindrone acetate
(NETAc) and ethinyl estradiol (EE) releasing rings were
also tested by the Population Council, but further develop-
ment was not pursued [3235].
4.2. NES/EE rings
Based on the excellent metabolic profile and the potent
antiovulatory effect of Nestorone, the Population Council
conducted several clinical trials testing a NES ring in
combination with EE [3638]. One 6-month study evaluated
rings releasing different NES/EE doses on a bleeding
signaled regimen. However, pregnancy rates were apparent-
ly higher than in the cyclic, 3-week in/1-week out, scheme
leading the authors to conclude that the menstrually signaled
regimen may be more difficult to comply with, due to
irregularity of frequent bleeding/spotting which led to
frequent ring removals which, in turn, may reduce
effectiveness [39,40].
In a dose-finding multicenter trial, three dose combina-
tions of NES/EE were compared in a ring prototype with a
duration of one year (NES 150/EE 15 mcg/d; NES 150/EE
20 mcg/d; NES 200/EE 15 mcg/day) [38]. These rings were
used on a 3-week in/1-week out regimen over 13 cycles of
use. The overall diameter of the silicone elastomer rings was
56 mm and 8.4 mm in cross-sectional diameter. All three
tested doses were effective, with no pregnancies reported in
the 150/15 and 150/20 doses. Bleeding control was excellent
as reflected in the very low 1 year discontinuation rate for
this reason (b2.5%). Device-related terminations accounted
for 4.09.7% of the discontinuations (expulsions or lost
rings). Colposcopy examinations documented the absence of
major vaginal or cervical problems during ring use [41]. User
satisfaction was high based on a one year continuation rate of
68-76% [38]. Based on this study, the ring releasing 150
mcg/d NES and 15 mcg/d EE, was selected as the lowest
effective dose of both steroids, for further development.
A large Phase III multicenter trial was launched by the
Population Council in 2006, with the primary objective of
evaluating the contraceptive efficacy and safety of the 1-year
150/15 mcg NES/EE contraceptive vaginal ring as the basis
for Food and Drug Administration (FDA) regulatory
approvals of this CVR as a new delivery system for
contraception. Cycle control, bleeding patterns, adverse
events, return to fertility and acceptability were also
evaluated. A total of 27 sites (20 in the USA, 3 in Latin
America, 3 in Europe and 1 in Australia) participated in this
trial that enrolled over 2000 women. In addition to the safety
and efficacy objectives, three safety sub-studies were
 V. Brache et al. / Contraception 87 (2013) 264272
conducted to evaluate the impact of the NES/EE CVR on
hepatic proteins, on microbiology, including vaginal micro-
flora and CVR flora, and on endometrial histology. Since
completion of this large trial, the Population Council is
preparing to submit a new drug application to the FDA
(Population Council, personal communication).
The feasibility of using this same prototype CVR as an
emergency contraceptive was also tested in 48 women.
Interference with the ovulatory process was observed in
87.5% of the cycles, suggesting that this ring may be used
as an emergency contraception method, with the potential
advantage of serving as a bridging method for the
continuous regular use of the CVR for 12 additional cycles
[42]. However, this method has not yet been developed for
the EC indication.
4.3. ENG/EE ring (NuvaRing)
In the early 1990s, several clinical dose-finding studies
with a combination ring delivering 3-keto-desogestrel and
EE, developed by NV Organon, Oss, The Netherlands, were
published [4346]. The prototype selected from these
studies is the NuvaRing (NV Organon, Oss, The Nether-
lands), a flexible, soft, multicompartment, transparent
vaginal ring made of ethinyl vinyl acetate, with an outer
diameter of 54 mm and a cross-sectional diameter of 4 mm.
The ring releases 120 mcg/day of ENG (the biologically
active metabolite of desogestrel) and 15 mcg/day EE. It is
intended for only one cycle of use (3 weeks in/1 week out), to
be replaced monthly. Women initiating use should insert
NuvaRing on the first day of the cycle. The ring need not be
removed for sexual intercourse or cleaning but it may be
removed for a maximum of 3 hours without loss of efficacy
if the user prefers so. NuvaRing was initially approved by the
FDA in October 2001 and is currently marketed in the USA,
Europe and many other countries.
After the insertion of NuvaRing, mean serum concentra-
tions of 1578 ng/L of etonorgestrel and 19.1 ng/L of EE were
achieved in approximately one week, with a slow, gradual
linear decrease with time. Systemic exposure to ENG is
similar between NuvaRing and an OC containing 150 mcg
desogestrel and 30 mcg EE, whereas systemic exposure to
EE with NuvaRing is about 50% of that for OCs [12].
Exposure to EE was 3.4 times lower (pb.05) with NuvaRing
than with the transdermal patch releasing 20 mcg EE (Evra,
Ortho-McNeil Pharmaceutical, Raritan, NJ, USA) and 2.1
times lower (pb.05) than a 30 mcg EE OC [47].
Inhibition of ovulation is the contraceptive mechanism of
action [48,49]. A recent study found that ovarian suppression
among users of NuvaRing was significantly higher than
among users of LNG/EE oral contraceptives. None of the
participants in either arm of the study had follicle rupture or
the presence of a corpus luteum [50].
Two large open-label, non-comparative, multicenter
registration studies were conducted in Europe, USA, and
Canada [51,52], while another two large open label,
267
randomized, Phase III studies, comparing NuvaRing with
OCs were also conducted in Europe and Latin America
[53,54]. Extensive reviews of all of these studies were
recently published by Roumen [55,56] and a Cochrane
review comparing vaginal rings with OCs was also updated
in 2010 [57].
NuvaRing studies have consistently shown high contra-
ceptive efficacy with no significant differences with OCs.
Pearl index (PI) have ranged from 0.251.23 pregnancies per
100 woman-years, in the large studies which enrolled
slightly over 3000 NuvaRing users, comparable to the
observed PI of 0.991.19 pregnancies per 100 woman-years
observed in the comparative arms of oral contraceptives (n=
1002 OC users). Continuation rates in the large noncom-
parative and randomized trials have been good, between
71% and 75% at 1 year, similar to pill users. Compliance was
above 85% for both ring and pill users, with higher
compliance in the European sites as compared to North
America. [5157].
One of the attractive features of NuvaRing is the
predictability of its bleeding patterns. In the non-comparative
large trials, the incidence of irregular bleeding was very low;
5.5% per cycle over Cycles 113 and very few women
discontinued due to bleeding irregularities [52,56]. Overall,
in the comparative trials, the incidence of breakthrough
bleeding was lower with NuvaRing (range 26%) as
compared with OCs (range 312%) [5761].
Several papers have been published regarding extended
use regimens of NuvaRing besides the recommended 28-day
cycle: a 49-day cycle (42 days of continued use (2 rings)/7
days out), a 91-day cycle (84 days in (3 rings)/7 days out) and
6 and 12 months of continuous use. In all studies, a reduction
of scheduled bleeding days was observed but with an increase
in breakthrough spotting days. The number of bleeding/
spotting days decreases during continuous use. These studies
show that extended use provides an acceptable bleeding
pattern and is an option for women willing to tolerate some
irregular spotting but with reduction in flow and fewer
withdrawal bleeding episodes [6265]. The most frequently
reported possibly related adverse events were headache, ring-
related issues, vaginitis, leucorrhea and nausea. However,
these individual complaints were reported with a low
frequency b8%. Discontinuations due to adverse events
were between 11% and 14% for NuvaRing users, slightly
higher than discontinuations among OC users (8.79.9%)
The only difference between the NuvaRing and OC users
were the higher incidences of local events such as leucorrhea,
vaginitis, vaginal discomfort and ring-related events (foreign
body sensation, coital problems, expulsions) [5154].
In an open-label, randomized, cross-over study designed
to investigate genital symptoms, signs and laboratory
findings with NuvaRing in comparison with a OC, 72% of
the women reported that the ring never slipped out
(expulsion), while in 9% the ring slipped out at least once
a week or more; 63% of NuvaRing users reported vaginal
wetness in comparison with 43% of OC users [66]. Fifteen to
268 V. Brache et al. / Contraception 87 (2013) 264272
eighteen percent of women reported feeling the ring during
sexual intercourse, while 2837% of their male partners also
felt the ring. Most partners did not object to ring use
[51,52,67].
Blood pressure remained unchanged in the non-compar-
ative studies and in most of the randomized studies for both
NuvaRing and OC users [47,49,51,54]. A slight mean body
weight increase of 0.843.81 kg over 13 cycles of treatment
was observed in the non-comparative study [52], while in the
comparative trial between NuvaRing and drospirenone/EE
pill, the changes were small for both groups with no
significant difference between methods [60].
No clinically relevant effect on bone mineral density, on
carbohydrate metabolism, adrenal or thyroid function has
been seen during NuvaRing use [6872].
No adverse effects were seen on endometrial histology
evaluated after 13 and 26 cycles of use. All biopsies presented
normal results, with atrophic or inactive endometrium and
secretory changes present in the majority of cycles [73].
Serious adverse events related to treatment were very few.
Two vaginal ring users had deep venous thrombosis (DVT)
although one of these women was heterozygous for Factor V
Leiden, which is associated with increased risk for venous
thrombosis. These DVTs were reported in two trials which
together enrolled 1011 ring users. Among the contraceptive
pill users, one had cholelithiasis and another hypertension
among 1002 enrolled pill participants [53,54].
Since CVRs are relatively new methods, limited infor-
mation is available on their safety, moreover so, among
women with specific medical conditions. The Medical
Eligibility Criteria for Contraceptive Use, Fourth edition
(2009) [74,75] states that the available evidence indicates
that combined rings have a comparable safety profile as
combined OCs (COCs); therefore, the same eligibility
categories apply to both rings and COCs.
5. Acceptability
Acceptability studies conducted among users of different
ring prototypes and among women from different cultures
have shown high user satisfaction. Convenience of use,
effectiveness and no requirements for taking medication
daily were among the most liked attributes of the
contraceptive ring [54,67,7679].
Studies carried out with the purpose of evaluating the
acceptance of the vaginal ring among users of an early
prototype LNG/E2 CVR have shown that women's control
over the method, inserting and removing it at their will
(during sex or to wash it) was appreciated as a positive
attribute of the ring not present in any other method. Many
women in the same study indicated that they believed it was
not hygienic to keep the ring for long periods in the vagina
without periodically cleaning it, a behavior they adopted on
their own as they had not been instructed to clean the ring,
except after an accidental expulsion. On the other hand, most
women did not feel the ring and many touched the genitals to
ensure that the ring was in place [76,77].
Acceptability studies among adolescents have shown that
once educated about the ring, a substantial percentage would
consider using it [80]. Willingness to use the ring was
associated with positive feelings about touching the genitalia
[81]. In a cross-over study comparing ring and oral
contraceptive use among adolescents, compliance was
similar, although 58% reported that correct pill use was
harder to remember than correct ring use (14%). However,
more women reported that the ring was more likely to
interfere with sex and that more sex partners liked the pill
(81%) than the ring (60%) [82].
User satisfaction with the vaginal ring was mostly higher
or similar to OC in randomized clinical trials that assigned
women to NuvaRing or low-dose OC while satisfaction was
higher with the ring than the hormonal transdermal patch
[54,83,84].
A recent study was conducted with the objective of
evaluating the effect of counseling women who were seeking
combined hormonal contraceptives about alternative hor-
monal methods. One out of four women who intended to use
the pill chose another method, and 65% of these chose the
ring. Ring use nearly quadrupled from 8% to 30%, with pre-
use counseling, indicating how counseling can influence the
uptake of different methods [85].
6. Effect of the vaginal route of delivery on hemostasis
variables and liver proteins
It has been postulated that the administration of estrogens
through the vaginal route would avoid the approximately
60% first-pass of the steroid through the liver that occurs
after oral administration [86]. The hypothesis was that the
same dose of estrogen administered vaginally would have
the desired effect on the central nervous system without
affecting hepatic metabolism as occurs after oral adminis-
tration. Unfortunately, studies comparing the effect of EE
administered orally and vaginally in equivalent dosages on
hepatic proteins, hemostasis variables and lipids, have failed
to show any difference between delivery route [8789].
These studies have provided evidence that the effects of
combined hormonal contraceptives on clotting factors and
markers of coagulation and fibrinolysis are largely due to the
EE component (with its high potency and slow metabolism)
and independent of the route of administration.
Several studies have compared hemostasis variables and
hepatic proteins, including sex hormone binding globulin,
between different CVRs and oral contraceptives. The
conclusion from these studies is that vaginal delivery of
combined hormonal contraceptives does not reduce the EE-
associated changes in estrogen-sensitive hepatic proteins
observed with OC use. EE impacts similarly on protein
synthesis whether delivered vaginally or orally, because of
the long half-life of EE. The differences between the LNG/
 V. Brache et al. / Contraception 87 (2013) 264272
EE OC comparison group and the two ring prototypes (NES/
EE and NuvaRing), is probably related to the androgenicity
of LNG, which opposes estrogen-dependent effects on the
liver [9093].
7. Future development of contraceptive vaginal rings
7.1. NES/E2 rings
All hormonal contraceptives containing EE have an
increased risk of venous thrombotic events [94]. Obesity on
its own also increases this risk, and has a synergistic effect
with the use of EE-containing OCs, greatly increasing the risk
[95,96]. A new contraceptive ring containing the progestin
Nestorone, but in combination with estradiol, a much lower
potency estrogen, will be evaluated in the Contraceptive
Clinical Trials Network of the National Institute of Child
Health & Human Development (NICHD), with the promise
of increased safety. This randomized, double-blind, dose-
finding study is designed to evaluate the effects of 3 different
doses of a NES/E2 CVR on cycle control, ovulation
inhibition and pharmacokinetics in normal cycling women.
Each CVR is designed for 3 months of continuous use, and
each subject will use 2 rings over a 6-month study [Clinical
Trials.gov Identifier: NCT01586000].
7.2. Progesterone receptor modulator rings
The Population Council in collaboration with HRA
Pharma (Paris, France) and with NICHD is developing a 3-
month CVR releasing the progesterone receptor modulator
(PRM), ulipristal acetate. This ring aims to provide an
estrogen-free contraceptive that does not require daily oral
intake. Ulipristal acetate, a derivative of 19-norprogesterone,
binds specifically to the human progesterone receptor. A
recent study reported inhibition of ovulation in 68% of the
cycles studied, concluding that further testing with higher
release rates of ulipristal acetate were required to attain
ovulation suppression in a higher percentage of cycles [97].
An updated review of these PRM rings is included in this
issue of Contraception [Jensen J, in this issue].
7.3. Multipurpose prevention technologies
There is an urgent need to develop technologies that
address multiple sexual and reproductive health needs,
including prevention of unintended pregnancy, prevention
of HIV and other reproductive tract infections, which
greatly affect women's health worldwide. Several organi-
zations are focusing on achieving this goal. Vaginal rings
would be an ideal delivery system for dual protection
methods because they provide controlled drug release over
extended periods of time with one, non-coital related
application, which could improve adherence and effective-
ness. The United States Agency for International Develop-
ment as well as The Bill and Melinda Gates Foundation are
strongly supporting these initiatives.
269
A cross-over study conducted by Hardy et al. [98] in
Brazil, evaluated women's difficulties and preferences with
three different devices that could possibly be used for
delivering microbicides: a diaphragm, an applicator and a
vaginal ring. Fifty-three percent of the women preferred the
vaginal ring, while 36% and 11% preferred the applicator
and diaphragm, respectively. Few women had problems with
inserting or removing the ring and the authors concluded that
the release of microbicides from a vaginal ring was a lead
worth pursing since it was well accepted by both women and
men and it was not coital-related.
The Contraceptive Research and Development Program
(CONRAD) has been conducting research for over 20 years
in developing contraceptive/anti-HIV technologies. Current-
ly, CONRAD is developing a 3-month intravaginal ring
releasing the antiretroviral tenofovir and levonorgestrel
(LNG). LNG was chosen because of its long track record
of safety and the available previous experience with the
WHO LNG-releasing ring [99].
The Population Council is also leading the development
of a combination ring containing the antiretroviral MIV-150,
zinc acetate, an antiviral agent with activity against HIV and
HSV, and the hormonal contraceptive LNG. The Population
Council has also partnered with the International Partnership
for Microbicides and has developed a prototype ring
releasing dapivirine together with LNG, but other progestins
are also being tested [100].
The reproductive health field awaits with great anticipation
the results of these research initiatives as they go thorough
preclinical testing, into clinical testing and finally into the
hands of women worldwide who are in great need of them.
8. Conclusions
Contraceptive vaginal rings are without doubt a welcome
addition to the available hormonal contraceptive methods.
Sustained and prolonged efforts of both public institutions
and a pharmaceutical company have succeeded in providing
women with a new contraceptive option, which is effective,
safe and highly acceptable to many women.
Some of the perceived advantages of the CVRs, regretfully
have not been demonstrated in clinical trials. It was thought
that not having to remember to take a pill every day, would lead
to better compliance and theoretically better effectiveness, but
comparative trials with OCs indicate that both methods have a
similar performance in this aspect. Also, the theoretical
advantage that administering EE by the vaginal route would
have less impact on liver proteins has also failed. The potential
of developing a combined NES/E2 ring, with a less potent
estrogen, has the promise of having much less impact on the
liver, and therefore providing safer contraception, most of all,
for overweight and obese women. However, the possibility of
less cycle control, may hinder acceptability. The ongoing
clinical trial will answer these questions.
The issue of cost is always of utmost importance in order
to assure accessibility to women. NuvaRing, a 1-month
270 V. Brache et al. / Contraception 87 (2013) 264272
disposable ring, may be convenient and affordable in some
settings, but hopefully, the NES/EE one-year ring, if
approved by the FDA, should be more cost-effective,
particularly in countries with greater economic restrictions.
Moreover, obtaining contraceptive protection for one year, in
a single clinic visit, should also have an impact on
effectiveness, because it is well known that many of the
contraceptive failures associated with oral contraceptives,
are due to the difficulty in obtaining monthly contraceptive
supplies, which is a similar situation as obtaining a monthly
ring. This impact is even greater in countries with logistic
limitations, in which there is not a constant availability of
contraceptives, and/or women have difficult access to the
centers providing these contraceptives. Therefore, the ideal
ring would have a one-year duration; however, this may not
be feasible for some steroids or compounds, due to
limitations in ring technology.
Overall, good acceptability of the CVR has been shown in
a large variety of countries and cultures around the world, yet
touching of the genitals and introducing an object in the
vagina may be an obstacle to use for women in some
cultures. It is important to understand and recognize that not
all methods are for all women and that individual preferences
will always exist. For many women, provider-dependent
long-acting contraceptives, such as implants, IUDs and
injectables are their choice, precisely because they do not
require any action or control by the user. On the other hand,
many women prefer to be able to control their contraceptive.
The vaginal ring is an excellent option for these women who
wish control, yet do not want a daily action as taking a
contraceptive pill, or women who do not like coital-related
contraceptives, such as diaphragms.
Current CVRs are not among the most popular contracep-
tive methods, in part because of lack of better promotion and in
part because of its cost and short duration of use. New
developments for the future, such as PRM-releasing rings,
which will provide estrogen-free contraception, as well as
combined rings in which EE is replaced by estradiol, both with
longer duration of use, as well as the 1-year NES/EE CVR,
have the potential for greater acceptance by the public. Another
important advance for the future is the dual protection vaginal
ring, which is most needed by so many women, who are
constantly at risk for both STIs and unintended pregnancies.
For all these reasons, we believe the vaginal ring technology
has not been explored to the broad extent of its promise and
will have an important, yet unexplored role in contraception.
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