Continuous oral

contraceptives versus long-

term pituitary
desensitization prior to
IVF/ICSI in moderate to
severe endometriosis: study
protocol of a non-inferiority
randomized controlled trial

L E E van der Houwen , M C I Lier,

A M F Schreurs, M van Wely, P G A Hompes,
A E P Cantineau, R Schats, C B Lambalk,
V Mijatovic

Human Reproduction Open, Volume 2019, Issue 1,

2019, hoz001,
https://doi.org/10.1093/hropen/hoz001
Published: 23 February 2019

Article history

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Abstract
STUDY QUESTIONS
The primary objective is to investigate if
continuous use of oral contraceptives is
non-inferior compared to long-term
pituitary desensitization with a GnRH
agonist prior to IVF/ICSI in patients with
moderate to severe endometriosis with
regard to treatment efficacy. Secondary
objectives concern treatment safety and
cost-effectiveness.

WHAT IS KNOWN ALREADY

Long-term pituitary desensitization with
a GnRH agonist for 3–6 months prior to
IVF/ICSI improves clinical pregnancy rates
in women suffering from endometriosis.
However, discussion about this treatment
strategy exists because of its
uncomfortable side effects. Alternatively,
IVF/ICSI pre-treatment with continuously
administered oral contraceptives may
offer fewer side-effects and lower
(in)direct costs, as well as encouraging IVF
outcomes in women with endometriosis.
To date, these two different IVF/ICSI pre-
treatment strategies in women with
endometriosis have not been directly
compared.

STUDY DESIGN, SIZE, DURATION

An open-label, parallel two-arm
randomized controlled multicenter trial is
planned, including patients with moderate
to severe endometriosis. To demonstrate
an absolute difference of 13% (delta of
10% with non-inferiority margin of 3%)
with a power of 80% 137 patients per
group are sufficient. Taking into account a
withdrawal of patients of 10% and a
cancelation rate of embryo transfer after
ovarian pick up of 10% (for instance due to
fertilization failure), the sample size
calculation is rounded off to 165 patients
per group; 330 patients in total will be
included. After informed consent, eligible
patients will be randomly allocated to the
intervention or reference group by using
web based block randomization stratified
per centre. Study inclusion is expected to
be complete in 3–5 years.

PARTICIPANTS/MATERIALS, SETTING,
METHODS
The research population consists of
patients with moderate to severe
endometriosis (ASRM III/IV) who are
scheduled for their first, second or third
IVF/ICSI treatment attempt. Women aged
over 41 years, younger than 18 years, with
a known contraindication for the use of
oral contraceptives and/or GnRH agonists
or with severe male factor infertility will
be excluded from participation. After
informed
Skip consent patients are allocated to
to Main Content
the intervention group (one-phase oral
contraceptive continuously during three
subsequent months) or the reference
group
Article (three Leuprorelin 3.75 mg i.m./s.c.
Navigation
depot injections during three subsequent
months). Tibolon 2.5 mg can be given
daily as add-back therapy in the reference
group. After 3 months of pre-treatment
the IVF/ICSI stimulation phase will be
started. The primary outcome is live birth
rate after fresh embryo transfer.
Secondary outcomes are cumulative live
birth rate after one IVF/ICSI treatment
cycle (including fresh and frozen embryo
transfers up to 15 months after
randomization), ongoing pregnancy rate
and time to pregnancy. In addition,
treatment outcome parameters, adverse
events, side-effects during the first 3
months, complications, recurrence of
endometriosis (complaints), quality of
life, patient preferences, safety and costs
effectiveness will be reported.
Measurements will be performed at
baseline and at 3, 6, 9, 12 and 15 months
after randomization.

STUDY FUNDING/COMPETING
INTEREST(s)
All authors have no conflict of interest
related to this manuscript. The
department of reproductive medicine of
the Amsterdam UMC location VUmc has
received several research and educational
grants from Guerbet, Merck and Ferring
not related to the submitted work.

TRIAL REGISTRATION NUMBER

The trial is registered as the COPIE trial
(Continuous use of Oral contraceptives as
an alternative for long-term Pituitary
desensitization with a GnRH agonist prior
to IVF/ICSI in Endometriosis patients) in
the Dutch Trial Register (Ref. No.
NTR6357, http://www.trialregister.nl).

TRIAL REGISTRATION DATE

16 March 2017.

DATE OF FIRST PATIENT’S

ENROLMENT
Enrollment is planned for November 2018.

Issue Section: Protocol

Introduction

Endometriosis is associated with subfertility in

up to 50% of patients (Meuleman et al., 2009).
In patients with severe endometriosis,
subfertility is presumed to be based on a
distortion of the pelvic anatomy, a hostile
peritoneal environment, a decreased oocyte
quality, a diminished ovarian reserve (due to
the presence of endometrioma or prior ovarian
surgery) and/or an impaired implantation due
to an altered endometrial receptivity (Giudice,
2010; de Ziegler et al., 2010a).

What this means for patients

Women with moderate to severe
endometriosis receiving IVF or ICSI are
nowadays advised to use a GnRH agonist
during 3 months before IVF or ICSI in
order to increase pregnancy rates. A
GnRH-agonist treatment could be
accompanied with unpleasant side effect
such as hot flushes and vaginal dryness. In
this study, we would like to investigate if
pre-treatment with an oral contraceptive
is as effective in pursuing pregnancy after
IVF or ICSI with lower side effects and less
costs.

Especially in cases of tubal dysfunction, in vitro

fertilization (IVF) or intracytoplasmic sperm
injection (ICSI) are stated as appropriate
treatments for subfertility in endometriosis
patients by the European Society of Human
Reproduction and Embryology (ESHRE)
guideline (Dunselman et al., 2014). However,
inferior success rates are especially described in
patients with moderate to severe endometriosis
(American Society for Reproductive Medicine
(ASRM) Stage III and IV) and in patients with
endometrioma(s) (Barnhart et al., 2002; Coccia
et al., 2011; Opoien et al., 2012; Johnson and
Hummelshoj, 2013).

To improve pregnancy rates after IVF/ICSI, it is

recommended to precede IVF/ICSI by long-
term pituitary desensitization with a GnRH
agonist for 3–6 months, since this is shown to
improve clinical pregnancy rates (CPR) (Dale et
al., 1990; Dicker et al., 1990, 1992; Nakamura et
al., 1992; Chedid et al., 1995; Rickes et al., 2002;
Surrey et al., 2002; Sallam et al., 2006; Ma et al.,
2008). However, the mechanism responsible
for this increase in clinical pregnancy rate is not
yet clarified and more research is needed.

Furthermore, as both the Cochrane and ESHRE

recommendations are based upon only three
small randomized studies (N = 165) (Dicker et
al., 1992; Rickes et al., 2002; Surrey et al., 2002),
executed in a different IVF/ICSI treatment era
in which more aggressive stimulation was used
and multiple embryos were transferred, debate
about this treatment strategy exists.
Additionally, different study-populations with
varying degrees of endometriosis (ASRM Stage
II–IV) were included in these trials (Dicker et
al., 1992; Rickes et al., 2002; Surrey et al., 2002),
which could have influenced the results.

It is also postulated that the use of a long-term

pituitary desensitization regime may lower
ovarian response to ovarian stimulation,
especially in poor responders (Griesinger et al.,
2008). In addition, uncomfortable side effects,
such as vasomotor instability, are often
reported by patients. These side effects might
result in a restrained attitude in prescribing this
treatment strategy for a longer period of time,
although add-back therapy is available to
diminish these vasomotor side-effects (Horn-
stein et al., 1998; Zupi et al., 2004). On the other
hand, patients who used long-term GnRH
agonists prior to IVF reported to be motivated
to use this treatment strategy again, despite
side-effects, in a next IVF/ICSI attempt (van
der Houwen et al., 2014a).

Alternatively, the effect of continued use of oral

contraceptives (OCs) for 6–8 weeks prior to
IVF/ICSI has been investigated (de Ziegler et al.,
2010b). Non-randomized data show that this
treatment is favourable in patients with severe
endometriosis undergoing IVF/ICSI, as clinical
pregnancy rates were higher compared to
endometriosis patients treated without OCs and
comparable to that of control patients without
endometriosis (de Ziegler et al., 2010b).
However, a randomized comparison between
continuous use of OCs and long-term pituitary
desensitization with a GnRH agonist prior to
IVF/ICSI in patients with endometriosis has not
yet been made.

The daily uncomfortable vasomotor side-

effects that are associated with a GnRH agonist
treatment without add-back therapy, are
negatively associated with work-ability and
increase the risk of sickness absence (Simoens
et al., 2011, 2012; Geukes et al., 2012; de Graaff et
al., 2013). It is currently unknown if this can be
positively influenced by using add-back
therapy.

Although the tolerability of OC is higher

compared to GnRH agonists (with or without
add-back therapy) (Berlanda et al., 2016), its
use is known to be often associated with
migraine, weight gain, depression and with a
higher risk on venous and arterial
thromboembolism (Hee et al., 2013, Beyer-
Westendorf, et al., 2018). By using OC
continuously, a reduction in monthly blood loss
is expected combined with a decrease in
dysmenorrhea compared to cyclic use of OCs.
However, this seems to be related with a higher
risk on spotting (Hee et al., 2013).

Due to potentially fewer side effects,

improvement of societal productivity can be
expected in women receiving continuous OC
treatment instead of GnRH agonist treatment.
Moreover, since GnRH agonists are over 40
times more expensive than OCs, a reduction in
directs costs of medication used in IVF/ICSI can
be achieved by prolonged use of OCs prior to
IVF/ICSI treatment.

Therefore, this study is conducted to

investigate if continuous use of OC is non-
inferior to long-term pituitary desensitization
with a GnRH agonist (as standard care)
combined with add-back therapy (if necessary)
prior to IVF/ICSI treatment, with regard to
treatment efficacy, safety and cost-
effectiveness.

Outcomes
The primary outcome is live birth rate after
fresh embryo transfer (ET). Secondary
outcomes are listed in Table I. Measurements
will be performed at baseline (t0), three (t1), six
(t2), nine (t3), twelve (t4) and fifteen (t5)
months after randomization.

Table I
Secondary outcomes.

Clinical – Cumulative live birth rate after

one IVF/ICSI treatment (number
of live births per initiated,
initiated cycle fresh and frozen
ETs up to 15 months after
randomization)

– Ongoing pregnancy rate

(positive heart action, confirmed
≥ 10 weeks after ET by TVS)

– Cumulative ongoing
pregnancy rate (including fresh
and frozen ETs up to 15 months
after randomization)

– Time to pregnancy (months)

Treatment – Follicular development (follicle

size distribution at the time of
hCG administration)

– Total dose and duration of

gonadotrophin treatment

– Number of oocytes and (top-

quality) embryos
(morphological assessment of
embryos: combining number of
blastomeres and percentage of
fragmentation)

– Fertilization rate (number of

fertilized oocytes per number of
retrieved oocytes)

– Implantation rate (number of

embryonic sacs observed by TVS
per number of transferred
embryos)

– Multiple pregnancy rate,

miscarriage rate, ectopic
pregnancy rate

– Endometrial thickness
(measured by TVS at the time of
hCG administration)

– Pain during oocyte pick up

(VAS 0–10 cm)

– Adverse events, complications

– Side effects of GnRH agonist

and continuous OC use during
the first 3 months

– Cancellation rate

Endometriosis – Recurrence of endometriosis

complaints within 15 months
after randomization

– Need for surgical/medical

treatment within 15 months
after randomization

– Quality of life (EHP-30)

– Patients’ preference of
treatment and treatment-
satisfaction (VAS 0–10 cm)

Cost- – Direct and indirect costs

effectiveness within 15 months after
and BIA
randomization (measured by the
iMCQ and iPCQ validated
questionnaires).

Factors to be – Patient characteristics (age;

taken into BMI; smoking; alcohol use;
account
hormonal treatment prior to
start of study; duration until
latest therapeutic surgery prior
to start of study; prior surgical
procedure; complete or
incomplete remediation of
endometriosis with prior
surgery; presence of
endometrioma and/or deep
endometriosis on ultrasound
and/or MRI; presence of
adhesions on ultrasound and/or
MRI and/or during previous
pelvic surgery; presence of
adenomyosis diagnosed
conform the MUSA criteria)

– Treatment characteristics
(first/second/third IVF/ICSI
attempt; other indications for
IVF/ICSI)

IVF = in vitro fertilization; ICSI = intracytoplasmic sperm

injection; EHP-30 = Endometriosis Health Profile 30; ET=
embryo transfer; hCG = human chorionic gonadotrophin;
TVS = transvaginal sonography; VAS = Visual Analogue
Scale; BIA = budget impact analysis; iMCQ = iMTA Medical
Consumption Questionnaire; iPCQ = iMTA Productivity
Cost Questionnaire; iMTA = Institute for Medical
Technology Assessment; MUSA = Morphological Uterus
Sonographic Assessment (van den Bosch et al., 2015); OC
= oral contraceptive.

Materials and Methods

The study will have a parallel two-arm

randomized controlled non-inferiority design
and will be open-label. Recruitment of patients
will be performed in two tertiary care centres in
the Netherlands. The research population will
consist of women with endometriosis ASRM
Stage III or IV who are scheduled for their first,
second or third IVF/ICSI treatment. The
diagnosis of endometriosis has to be surgically
confirmed or likely to be present based on
transvaginal sonography (TVS) or magnetic
resonance imaging (MRI) findings, including
the presence of uni- or bilateral ovarian
endometrioma and deep endometriosis. For
diagnosing endometrial cysts and/or deep
endometriosis diagnostic classification systems
for imaging modalities like sonography and/or
MRI do not exists, although guidelines help
clinicians in describing sonographic findings in
a structural way (Guerriero et al., 2016). Clinics
involved in this study will use the systematic
approach for sonography as presented by the
IDEA group (Guerriero et al., 2016). Sonography
and MRI are both shown to be accurate enough
to diagnose endometrial cysts in the ovaries
and deep endometriosis in the lower bowel and
other pelvic structures (Nisenblat et al., 2016).
Also women with surgically treated (i.e.
remediated) moderate to severe endometriosis
will be included. Excluded from participation
will be women aged under 18 and over 41 years,
women with a known contraindication for the
use of OCs (history of venous
thromboembolism (VTE), hepatic adenoma(s),
positive family history for VTE and/or known
thrombophilic abnormalities (Middeldorp,
2011)) or for the use of GnRH agonists (severe
side-effects and/or allergic reaction to GnRH
agonists), pregnant women, women with a
malignancy or severe male factor infertility (i.e.
azoospermia). Non-Dutch speaking women will
be excluded. Women can only participate once
in the study.

The study schedule is presented in the Consort

Flow Diagram (Fig. 1). Before study entry,
women will be screened for eligibility. Women
who comply with all selection criteria will be
informed about the trial during a visit at the
outpatient clinic or IVF centre. Information will
be handed out by a gynaecologist, resident,
fertility physician or research nurse offering a
reflection time of minimally 7 days. Informed
consent must be signed before any study-
related procedures can be carried out. After
informed consent is obtained, women will be
randomly assigned to the intervention group
(one-phase oral contraceptive continuously
administered during three subsequent months)
or the reference group (three GnRH agonist
depot injections during three subsequent
months combined with add-back therapy if
necessary). Randomization will be performed
via web based randomly permuted blocks with
variable, randomly chosen sizes (4–6–8
patients) stratified by participating centre.
Drop outs after randomization will not be
replaced.

Figure 1

View large Download slide

Consort Flow Diagram and study schedule. CRF = case

record form; EHP-30 = Endometriosis Health Profile 30;
GnRH = gonadotropin releasing hormone; ICSI =
intracytoplasmic sperm injection; iMCQ = iMTA Medical
Consumption Questionnaire; iMTA = institute for Medical
Technology Assessment; iPCQ = iMTA Productivity Cost
Questionnaire; IVF = in vitro fertilization; n = number; t =
time point; TVS = transvaginal sonography.

After randomization, at baseline (t0) a TVS will

be performed, to determine the presence of
endometrioma and signs of deep
endometriosis. Baseline characteristics and
medical history will be listed in the case report
file (CRF). Participants will be asked to
complete different questionnaires at baseline
(t0), three (t1), six (t2), nine (t3), twelve (t4)
and fifteen (t5) months after randomization.
These validated questionnaires measure quality
of life of women with endometriosis
(Endometriosis Health Profile 30 (EHP-30)
(Jones et al., 2004)), direct and indirect medical
costs (the Medical consumption Questionnaire
(iMCQ) (Bouwmans, 2013a) and the
Productivity Cost Questionnaire (iPCQ) (Bouw-
mans, 2013b)). During the first 3 months of
treatment medical consultation, side-effects
and absence of work will also be recorded in a
patients’ diary.

All women in the intervention group will

receive one-phase oral contraceptives (sub-50
OCs) continuously administered during three
subsequent months (i.e. 3 × 28 days). Preferably
ethinylestradiol/levonorgestrel 30/150 µg is
prescribed. Since a lot of patients already use
specific types of OCs, other one-phase sub-50
OCs will be accepted as well. Women will be
instructed to contact the IVF department on the
first day of bleeding after stopping the OC (after
3 months) treatment. On day two of the
withdrawal bleeding women will visit the IVF
centre and Triptorelin ‘Decapeptyl’ s.c. will be
started for suppression of the luteinizing
hormone (LH) peak. One day later ovarian
stimulation will be started with subcutaneously
injected gonadotrophins (follicle stimulation
hormone (FSH)) in an individually determined
dosage.

All women in the reference group will receive

three Leuprorelin ‘Lucrin’ 3.75 mg i.m. or s.c.
depot injections during three subsequent
months. During these months Tibolon ‘Livial’
2.5 mg tablets can be given daily as add-back
therapy. Women will have an appointment at
the IVF department exactly 28 days after the
last Leuprorelin injection. According to