Review of the literature on the use or not the use of the Oral contraceptive pill in pre-treatment of GnRa-antagonist protocols in IVF cycles

1. To pill
in the GnRH-
antagonist cycles
MD PhD Candido Tomás
Ovumia/Fertinova • Finland
Denmark 3.8.2017
or not to pill?

2. Outline
Antagonist protocols
Rationale for the use OC
Scheduling of cycles
Synchronisation of follicle growth
Clinical results
Conclusion

3. Introduction of GnRH-antagonist protocols
Long
GnRh-agonist
Protocol
GnRh-
antagonist
Protocol
Agonist
Antagonist
Gonadotrophins
Gonadotrophins
shorter
treatment
no
flare-up
effect
no
withdrawal
effects
lower
risk of
OHSS
Pre-treatment cycle Treatment cycle
longer
treatment
flare-up
effect
pituitary
suppression
lower
cyst risk
less
consumption
of gn.
similar
live birth
rates
Devroey et al., Hum Reprod 2009; Al-Inany et al., Hum Reprod Update 2011

4. Long
GnRh-agonist
Protocol
GnRh-
antagonist
Protocol
Agonist
Antagonist
Gonadotrophins
Gonadotrophins
shorter
treatment
no
flare-up
effect
no
withdrawal
effects
lower
risk of
OHSS
Pre-treatment cycle Treatment cycle
longer
treatment
flare-up
effect
pituitary
suppression
lower
cyst risk
less
consumption
of gn.
similar
live birth
rates
Scheduling of
treatmentPre-treatment
• OC
• E2, P, GnRh-
Antagonist
Follicle
synchronicity
Introduction of GnRH-antagonist protocols

5. Challenges related with the use of
GnRH-antagonist protocols
• Planning of the treatment: distribution of work-load during
the week; work during week-ends
• Antral follicle sizes are heterogeneous at initial follicular
phase and may have asynchronous growing
• More critical when there is a small no. of follicles (poor
responders)
• Initial reports suggested a tendency for fewer mature
follicles, oocytes and embryos with antagonist protocols
• Clinical results
Cédrin-Durnerin I et al, Hum. Reprod 2007; Guivarc’h-Levêque A et al. Fertil Steril 2011; Nielsen E et al.
Mol Hum Reprod 2011; Al-Inany HG et al. Cochrane Database Syst Rev 2001.

6. There is evidence that the destiny of each follicle dependents from a balance between the expression
and action of factors promoting follicular growth and those promoting apoptosis.
more than 175 days
Gougeon A, Hum Reprod 1986; Gougeon A, Ann d’Endocrinol 2010; Baerwald et al., Hum Reprod Update
2012; Nielsen et al. Mol Hum Reprod 2011; Nassar et al. Fertil Steril 2016.
Ex: androgens have a facilitating role for follicle responsiveness to FSH
Follicular development: continuous, cohorts or waves

8. 1.Planning ovarian stimulation and
oocyte retrieval in IVF programs
Barmat L et al. Fertil Steril 2005

9. Alternatives for cycle control
• Use of estrogens in late luteal phase
• Progestogen alone in late luteal phase
• Late luteal phase GnRh-antagonists
• Starting day of stimulation protocol
• Timing of ovulation triggering
Cedrin-Durnerin I et al. Fertil Steril 2012; Blockeel C et al., RBMOnline 2012; Griesinger G & Kolibianakis EM
RBMOnline 2012; Tremellen KP & Lane M, Hum Reprod 2010; Fanchin R Fertil Steril 2004

10. Cycle day 2 Transvaginal US
hormonal profile (if desired)
Cycle day 2/3 Start FSH 150–200 IU. Continue
Stimulation days 5–6
Start GnRH antagonist administered daily. Continue
3 follicles 15–19 mm
Day of triggering
• Ensure interval between antagonist and hCG does not exceed 30 h
• hCG 5000–10000 IU
Oocyte retrieval
Monitoring according to clinic practice
• US (+ blood test if required)
• FSH dose adjustments may be consideredDuration of treatment based on
clinical judgement in
consultation with patient
(usually 2 USs)
For regular IVF patients:
• 5–9 small follicles per ovary
• Age < 35 years
• No PCOS
• No history of poor responses
• No endometriosis
This suggested protocol represents a ‘best estimate’
given current data and clinical experience
Devroey et al. Hum Reprod 2009;24:764

11. Ovulation triggering
• At least 3 follicles of 17 mm
(Borm et al 2000; Fluker 2001; Kolibianakis 2002, 2003)
• At least 3 follicles of 18 mm (Garcia-Velasco 2001)
• Leading follicle of 18-20 mm and estradiol levels
(Olivennes 1998)
• At least 1 follicle of 18 mm and 3 follicles of 15mm
(de Jong 2001)
• At least 1 fol 20mm and E of 1200 pg/ml (Albamo 2000)

12. • Retrospective analysis of 1642 cycles
• Two or more follicles ≥17 mm in diameter

13. 2.Different follicular size and
asynchronous development
• Antagonist protocols: Some studies suggested fewer mature follicles,
oocytes and embryos
• There are differences in the characteristics of the small antral follicle cohort
(2-8 mm) before gonadotropin stimulation. Different sensitivity to FSH
• A possible explanation for this phenomenon involves the exposure of small
antral follicles to gradient FSH levels during the late luteal phase.
• This feature is exacerbated in older women and in patients presenting
ovarian function defects and short menstrual cycles.
• This may reduce the number of viable oocytes and embryos, thereby
altering adequate embryo selection. This is a determining factor for
achieving a live birth
Nassar J et al. Fertil Steril 2016; Fanchin R et al. Hum Reprod 2003; Gougeon A et al. J Reprod Fertil 1983; 1.
Depalo R et al. RBMOnline 2012

14. Poor responders
• There is no evidence of improved ovarian response by the use of OC in
antagonist cycles for poor responders
• N=82 poor responders
Kim CH et al. Fertil Steril 2009

15. 3.Clinical results
• Initial studies suggested that OC before ovarian stimulation was associated
with an increase in the number of oocytes retrieved and improved IVF-ET
outcome (Huirne et al. RBMOnline 2006; Rombauts et al. Hum Reprod 2006)
• Other recent studies suggest that the use of OC pretreatment is associated
with a diminished IVF-ET outcome (Cedrin-Durnerin et al. HR 2007;
Kolibianakis et al. HR 2006)
• Meta-analysis of RCT (2008, updated in 2010) in GnRh-antagonist protocols
pretreated or not with OC shows:
• increased gonadotropin consumption
• an increased duration of stimulation
• a reduction in ongoing pregnancy rate
Nassar J et al. Fertil Steril 2016; Griesinger G et al. Fertility and Sterility 2010

16. Griesinger G et al. Fertility and Sterility 2010
Rate difference:
-5% [-10% to -1%; P=.02]
Meta-analysis (updated)
• 6 randomised studies
• Stimulation after 5 days of OC or 2-3 days after a spontaneous bleeding
• In this updated meta-analysis 1,343 randomized patients on OC pretreatment in GnRH
antagonist cycles are available
ongoing pregnancy
Duration of stimulation:
+1.33 days, [0.61–2.05; P<.01]
stimul. duration

17. Griesinger G et al. Fertility and Sterility 2010
Gonadotropin amount
+360 IU [158–563, p<0,01]
Number of oocytes
+0.6 oocyte [CI: -0.08–1.25]

18. Reasons for OC effect
• Unclear reasons that could explain the lower clinical
results with OC pill:
• The gestagen component of the OC pill may produce a
negative impact on the endometrial receptivity in the
subsequent cycle
• A decrease in endogenous LH may be associated
with impair oocyte quality or endometrial receptivity
Griesinger G et al. Fertility and Sterility 2010

19. Controversy…
• Care when taking conclusions from meta-analysis (methodological erros)
• only 6 of 34 studies included
• inclusion of normo- and poor responders
• low no. of recruited patients in some studies
• various formulations of OCP and of different duration
• Varying wash-free OC period 2-5 days
• Wash-out of 5 days between ending OCP and starting stimulation
• Reducing duration of OC use
Garcia-Velasco J & Fatemi H, RBMOnline 2015; Griesinger G et al. RBMOnlne 2015.

20. Resume
• Meta-analysis seems to show that OC associated with GnRh-antagonist
cycles results in lower ongoing pregnancy rates, a need for more
gonadotrophin use and results in similar no. of oocytes in comparison with
GnRh-antagonist cycles without OC
• The desired effects of OC in GnRh-antagonist cycles may be obtained by
other alternative means
• Alternatives for cycle control: progestogen or oestrogen alone in the luteal
phase; late luteal phase GnRH-antagonist; timing of ovulation triggering
• If OCP is going to be used, reduce its duration and respect a wash-out
period of 5 days
• Further well designed studies can clarify the possible benefits of OC
associated with GnRH-a protocols

21. Review
Management of ovarian stimulation for IVF: narrative
review of evidence provided for World Health
Organization guidance
Cindy Farquhar a
, Jane Marjoribanks a,
*, Julie Brown a
,
Bart CJM Fauser b
, Anne Lethaby a
, Selma Mourad c
, Robert Rebar d
,
Marian Showell a
, Sheryl van der Poel e
a
Department of Obstetrics and Gynaecology, University of Auckland, Auckland 1142, New Zealand
b
Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands
c
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
d
Western Michigan University Homer Stryker MD School of Medicine, Michigan, USA
e
Reproductive Health and Research Department, World Health Organization (WHO), Geneva, Switzerland
Cindy Farquhar is Postgraduate Professor of Obstetrics and Gynaecology in the Department of Obstetrics and
Gynaecology at the University of Auckland, and Coordinating Editor of the Cochrane Gynaecology and Fertility
Group. Her research interests include clinical trials related to subfertility and gynaecology, systematic reviews,
clinical practice guidelines and quality improvement.
KEY MESSAGE
Evidence on 10 critical clinical questions concerning the management of ovarian stimulation for women un-
dergoing IVF was reviewed. In this paper, an evidence summary and draft recommendations provided to World
Health Organization guideline development groups reviewing global guidance are presented.
A B S T R A C T
In this paper, a review of evidence provided to the World Health Organization (WHO) guideline development, who prepare global guidance on the man-
agement of ovarian stimulation for women undergoing IVF, is presented. The purpose of ovarian stimulation is to facilitate retrieval of multiple oocytes
during a single IVF cycle. Availability of multiple oocytes compensates for inefficiencies in subsequent stages of the cycle, which include oocyte matu-
ration, IVF, embryo culture, embryo transfer, and implantation. Multiple embryos can be transferred in most women, and spare embryos can be frozen
to allow for future chances of pregnancy without the need for repeated ovarian stimulation and oocyte retrieval. Our evidence synthesis team ad-
dressed 10 clinical questions on management of ovarian stimulation for IVF, prepared a narrative review of the evidence and drafted recommendations
to be considered through WHO guideline development processes. Our main outcome measures were live birth, clinical pregnancy, and ovarian hyper-
Farquhar C et al., RBMOnline 2017; Farquhar C et al. Cochrane 2017

22. •OC before GnRh-antagonist cycles helps to
synchronize the development of the follicular cohort
and aid planning of IVF cycles
•Reduce cyst formation
•A Cochrane systematic review addresses
this question (Farquhar et al., 2017):
•was associated with fewer ongoing pregnancies (OR
0.70, 95% CI 0.54-0.91; moderate quality evidence)
•Associated with more treatment days and a higher
amount of gonadotrophin therapy (very low-quality
evidence)
Farquhar C et al., RBMOnline 2017; Farquhar C et al. Cochrane 2017

23. thank you…
candido.tomas@ovumia.fi
not to the pill…