Progestin-primed ovarian stimulation (PPOS) is a NEW DAWN in ovarian stimulation protocol in IVF. Dr Sharda Jain

1. Progestin-primed ovarian stimulation (PPOS)
is a NEW DAWN in
ovarian stimulation protocol in IVF.
DR. SHARDA JAIN
DR. JYOTI AGARWAL

3. Over the past few years, the research has
focused on the replacement of GnRH
analogues by Progestins for controlling
the premature LH surge.

4. Contents
• Need for Pituitary suppression in ART cycle
• Various Drugs being used for Pituitary
Suppression-Agonist, Antagonists
• Why Progesterone for pituitary suppression ?
• Clinical Studies
• Future role

5. • GnRH in a pulsatile Hormone from HT
• Pituitary  LH and FSH,
• Luteinizing hormone (LH) stimulates the theca cells to
produce androgen, which is then converted to estrogen
• Upon achieving a critical level of estradiol it begins to have a
positive feedback on LH release, which results in an “LH
surge” that initiates ovulation
Hypothalamus Pituary -ovarian axis,
with the positive and negative feedbacks of estrogens and progesterone

6. Hypothalamus
Pituary - Ovarian
axis,
with the positive
and negative
feedbacks of
estrogens and
progesterone

7. Need for Pituitary Suppression in ART Cycle
• Premature LH surge ( 21% to 25%) is a major cause
for cycle cancellation during COS in women
undergoing IVF without intervention
• Thus premature LH surge should primarily be
prevented

8. Long & Short Protocol for
Pituary Suppression
GnRH agonists
(LONG Protocol)
are available for use in ART and
they exert an initial stimulatory
effect on gonadotropin
secretion, which leads to the so-
called ‘flare effect’
A pretreatment interval of 10-14
days is required to allow the
flare effect to subside before
gonadotropin treatment may
begin
GnRH antagonists
(Short Protocol)
offer a therapeutic alternative
to agonists for pituitary
suppression
GnRH antagonists achieve an
immediate and dose-dependent
suppression of LH by competing
with native GnRH to bind to
pituitary cell membrane
receptors

9. LONG
PROTOCOL
Long GnRH Agonist Protocol

10. *High Costs
*Daily Subcutaneous Injections
WHY ALTERNATIVE TO
ANTAG PROTOCOL USING
Conventional ANTAGONIST

11. Progesterone for Pituitary suppression -
Mechanism of action
 Progesterone is a key signal in the mid-cycle dynamic
 exact mechanisms through which progesterone interacts
with estradiol to regulate the LH surge is not known
 A critical factor is there which controls progesterone’s effect
upon the preovulatory gonadotrophin secretion, i.e.
whether it is stimulating or inhibiting, or its timing of
administration  is not fully understood
Hum Reprod Update. 2021 Jan 4;27(1):48-66.

12. Endogenous progesterone could hinder the rise of
LH  no spontaneous LH surge occurred during COS
in the luteal phase shows in few studies.
Progesterone reduces GnRH’s pulsatility from the
hypothalamus, thus inhibiting the LH release
associated with increased estradiol levels.
Therefore, a new strategy for COS, i.e., PPOS was
gradually investigated.
Facts known about Progesterone

13. • When IVF relied on fresh ET, P4 could not be
considered for use during COH because it was
known to have a negative impact on endometrial
receptivity
• FET CYCLES  it has become feasible to use
Progestin as an alternative agent for the
suppression of premature LH surge during COS
Why Progesterone was
not used in IVF PROTOCOLS

14. Organization of a conventional ovarian stimulation (COS)
protocol with a GnRH antagonist, versus a progestin primed
ovarian stimulation (PPOS) protocol.
Million Dollar Slide
Antonio La Marca et.al., Reprod Biomed Online. 2019 Aug;39(2):321-331.

15. Reprod Biomed Online. 2019 Aug;39(2):321-331.

16. Progestin-primed ovarian stimulation (PPOS)
New Dawn
Oral administration of exogenous
progesterone, beginning in the early follicular
phase is used in IVF treatments.
Cui L et al. Archives of Gynecology and Obstetrics. 2021 Mar;303(3):615-30.

17. Progestin-Primed Ovarian
Stimulation  Let’s RECAP
Blocks the luteinizing hormone (LH) surge through
progesterone instead of traditional down regulating
or gonadotropin-releasing hormone (GnRH)
antagonist.
PPOS can effectively serves as an alternative
to conventional treatment with GnRH
analogs
Cui L et al. Archives of Gynecology and Obstetrics. 2021 Mar;303(3):615-30.

18. #1 Durdag et al.Turk Ger Gynecol Assoc 2021
Review
of
Literature
The efficacy of Dydrogesterone use to suppress
premature luteinizing hormone surge on cycle
outcomes in controlled ovarian stimulation

19. USE of Dydrogesterone use to suppress premature
luteinizing hormone surge on cycle outcomes in
controlled ovarian stimulation

20. • Dydrogesterone (Duphaston® 10 mg, Abbott Pharma,
Netherlands) 2x20 mg/day was started when the
dominant follicle reached 12 mm in diameter or
serum estradiol was over 300 pg/mL and continued
till trigger day
• 105 women participated in the study, of whom 52
were included in the dydrogesterone group and 53 in
the GnRH ant group

21. • Duration of pituitary suppression was longer in
Dydrogesterone group.
• Premature ovulation was observed in 11.5% (6/52) and 0%
in the Dydrogesterone and GnRHant groups, respectively.
• Collected oocyte counts and metaphase II oocyte counts
were found to be similar between the groups.
• Dydrogesterone can be used as an alternative to
antagonist regimen in patients where embryo
transfer is not planned in the same cycle.

22. #2 Gurbuz AS et al. J. Obstet. Gynaecol. Res. 2020
Review
of
Literature
Dydrogesterone-primed ovarian stimulation is an effective
alternative to gonadotropin-releasing hormone antagonist
protocol for freeze-all cycles in polycystic ovary syndrome

23. • Sample size: Retrospective analysis of 525 PCOS patients
who underwent FET
• DYD-primed ovarian stimulation (20mg) and a GnRH
antagonist protocol were applied in 258 and 267 patients,
respectively

24. • There was no significant difference in clinical pregnancy rate of the
first frozen embryo transfer cycle between the DYG group and the
CET group (56% [120/214] vs. 55.6% [113/203], respectively, P =
0.283).
• There were no significant differences in biochemical pregnancy
rates, implantation rates, miscarriage rates or ongoing pregnancy
rates between the two groups (P > 0.05)
• Dydrogesterone-primed ovarian stimulation
seems to be an effective alternative to the GnRH
antagonist protocol for freeze-all cycles in PCOS
patients

25. #3 Huang J et al. Drug Design, Development and
Therapy 2019
Review
of
Literature
Neonatal outcomes and congenital malformations in
children born after dydrogesterone application in progestin-
primed ovarian stimulation protocol for IVF:
a retrospective cohort study

26. • Sample Size: retrospective cohort study included 3556 live-born
infants after IVF using the DYG (20 mg) + hMG protocol (n=1429) or
gonadotropin-releasing hormone (GnRH)-agonist short protocol
(n=2127)
• Newborn information was gathered from standardized follow-up
questionnaires and/or access to medical records within 7 days
after birth.

27. • For adverse neonatal outcomes, the two protocols showed no
significant differences on the rates of low birthweight, very low
birthweight, preterm birth, very preterm birth, small-for-gestational
age, large-for-gestational age and early neonatal death after
adjustment.
• The incidence of major congenital malformations in the DYG + hMG
protocol was similar to that in the GnRH-agonist short protocol
• DYG in the PPOS protocol was a safe option for the
newborn population without compromising
neonatal outcomes or increasing congenital
malformation risks.

28. #4 Iwami N et al. Archives of
Gynecology and Obstetrics (2018)
Review
of
Literature
New trial of progestin-primed ovarian stimulation using
dydrogesterone versus a typical GnRH antagonist regimen in
assisted reproductive technology

29. • Sample Size: prospective, controlled study of 251 women who
underwent COH . The patients were allocated alternately into two
groups: a dydrogesterone 20 mg/day protocol (study group) and a
GnRH antagonist protocol (control group).
• None of the patients experienced a premature luteinizing hormone
surge
• Ongoing pregnancy rates at 12 weeks were 40.0% in study group versus
38.1% in control group
• The clinical pregnancy rate in study group (52.8%) was also not inferior
to that in control group (49.5%)
• The clinical and ongoing pregnancy rates in DYD
group were comparable to those in control group.

30. #5 Yu S et al. Human Reproduction 2018
Review
of
Literature
New application of dydrogesterone as a part of a progestin-primed
ovarian stimulation protocol for IVF: a RCT
including 516 first IVF/ICSI cycles

31. • A prospective RCT including 516 patients into two treatment groups: an
hMG + DYG group 20mg (260 patients) or an hMG + MPA group (256 patients)
followed by IVF or ICSI with the freeze-all strategy.
• There was no significant difference in the number of oocytes retrieved
• During the whole process of ovarian stimulation, the mean LH level in the hMG +
DYG group was always higher than that in the hMG + MPA group (P < 0.001)
• No significant difference was found in the clinical pregnancy rate of the first FET
cycle between the two
• DYG, which exhibits no or weak inhibition of ovulation at a
normal dosage, can serve as an hMG adjuvant during ovarian
stimulation.

32. #6 Rashidi BH et al Journal of Family and
Reproductive Health 2020
Review
of
Literature
Comparison of Dydrogesterone and GnRH Antagonists for
Prevention of Premature LH Surge in
IVF/ICSI Cycles: A Randomized Controlled Trial

33. • RCT with 200 women undergoing IVF/ICSI were randomly assigned into
two groups.
• HMG was administered for controlled ovarian stimulation (COS) in both
groups.
• Group 1: 20 mg dydrogesterone from day 2 of menstrual cycle till trigger
day
• Group2 control: received GnRH antagonist from the day that leading
follicle reached 13 mm in diameter till trigger day.

34. • None of the patients in two groups experienced a premature luteinizing
hormone surge.
• The numbers of retrieved oocytes, the MII oocytes and good quality
embryos, were significantly higher in the intervention group than
antagonist group (p < 0.05).
• The overall chemical pregnancy rate in intervention group (43/91: 46.2%)
and control group (45/91: 49.5%) (p = 0.820) was similar.
• Efficacy and easy usage of dydrogestrone, it may be reasonable to
use it as an alternative to GnRH antagonist for the prevention of
premature LH surge.

35. Clinical efficacy of Progesterone Primed Ovarian
Stimulation (PPOS) using MPA
Kuang et al., conducted the first study in 2015
Objective: To investigate medroxyprogesterone acetate (MPA) to prevent LH surge
during COH and to compare cycle characteristics and pregnancy outcomes in
subsequently frozen-thawed ET (FET) cycles
Study Design: Prospective controlled study
Patients: 300 patients undergoing IVF/ICSI
Interventions: Study group - hMG and MPA; Ovulation was induced with a GnRH agonist
or co-triggered by a GnRH agonist and hCG when dominant follicles matured. Control
group - Short protocol
Fertil Steril. 2015 Jul;104(1):62-70.e3.

36. Clinical efficacy of Progesterone Primed Ovarian
Stimulation (PPOS) using MPA
Outcome measures: Primary outcome - Number of oocytes retrieved
Results:
1. Oocytes – Study group vs. controls (9.9 ± 6.7 vs. 9.0 ± 6.0)
2. LH suppression persisted during ovarian stimulation, and the incidence of
premature LH surge was 0.7% (1/150)
3. Clinical pregnancy rates (47.8% vs. 43.3%), implantation rates (31.9% vs.
27.7%), and live-birth rates (42.6% vs. 35.5%) in the study group and
controls respectively, were similar
Fertil Steril. 2015 Jul;104(1):62-70.e3.

37. Kuang et al., study – 2015
USING MPA
Fertil Steril. 2015 Jul;104(1):62-70.e3.
Conclusions: MPA is an effective oral alternative for the prevention of
premature LH surge in woman undergoing COH

38. AIVF - Poster Presentation at
ASRM 2022
By Dr KD Nayar & Group

39. PROGESTERONE PRIMED OVARIAN STIMULATION PROTOCOL (PPOS) Vs GNRH ANTAGONIST FOR PATIENTS OF FREEZE ALL CYCLES: A
PROSPECTIVE RANDOMISED CONTROLLEDTRIAL
Kanad Dev Nayar, Shweta Gupta, Sabina Sanan, Sumita Agarwal, Garima Kaur, Kanika Sharma, Gaurav Kant, Kapil Dev Nayar
Akanksha IVF Centre, Delhi, India
OBJECTIVE: RESULTS:
To compare effectiveness of Progesterone vs GnRH
Antagonist for pituitary suppression in controlled ovarian
stimulation for patients of Freeze all IVF/ICSI cycles
MATERIALS AND METHODS:
The number of oocytes retrieved were slightly more
in PPOS group (12.4 ± 2.6)than in antagonist
group(11.8 ± 2.2), difference was not statistically
significant. Consequently the no. of mature oocytes,
no. of fertilized, cleaved and cryopreserved embryos
were also similar. The total dose of gonadotropins
used and duration of stimulation were comparable in
the 2 groups. No early ovulation was observed in
either group. Although 1 patient in the antagonist
group had symptoms of mild OHSS. Overall
pregnancy outcomes were statistically comparable,
implantation rate (29.67% in the PPOS group vs.
26.08% in the antagonist group), clinical pregnancy
rate (38.6% in the PPOS group vs. 40.2% in the
antagonist group), Biochemical pregnancy rate (54 %
in the PPOS group vs. 50% in the antagonist group)
and miscarriage rate (10.8% in the PPOS group vs.
11.4% in the antagonist group).
Primary outcome: Number of oocytes retrieved
Secondary outcomes: Duration and Dosage of
Gonadotropins, Number of MII oocytes, No. of
fertilized oocytes, No. of cleaved and cryopreserved
embryos, incidence of OHSS, Implantation rate,
Clinical pregnancy rate, Miscarriage rate and
Biochemical pregnancy rate. Data analyzed using
SPSS version-17 and using chi-square test for
categorical variables and unpaired t-test for
continuous variables.
Outcome Group 1
(PPOS)
Group 2
(Antagonist)
P value
Oocyte
Retrieved
12.4 ± 2.6 11.8 ± 2.2 NS
Implantati
on Rate
29.67% 26.08% NS
Clinical
pregnancy
38.6% 40.2% NS
Miscarriag
e
10.8% 11.4% NS
Mild OHSS NIL 1
.
Prospective Randomised controlled trial
conducted from 1st April 2021 to 28th March
2022 at a tertiary care infertility centre Akanksha
IVF centre, New Delhi. 80 infertility patients age
between 23-37years with normal uterine cavity
by 2D ultrasound/ hysteroscopy were enrolled
and randomized into 2 groups of 40 each by a
computer generated program. Study Group
(n=40) patients were given Tab
medroxyprogestrerone acetate 10mg once daily
from day 1 of stimulation. Control Group(n=40)
received GnRH Antagonist Inj. Cetrorelix 0.25mg
s/c on Day 6 of stimulation according to fixed
protocol. TVS monitoring started on day 2 of
menses along with gonadotropins. When > 2
follicles reached the size of 18 mm, all patients
received Inj Leupride 2mg subcutaneously as
trigger for final oocyte maturation. Oocyte
retrievals were performed at 35 - 36 hours. Day 3
Frozen embryo transfers (3x 8cellA) was
performed for all cases. The luteal phase support
was with vaginal supplementation of 800 mg
micronized progesterone. Serum beta hCG was
performed after 14 days of embryo transfer.

40. CONCLUSIONS:
PPOS can achieve similar embryological and clinical
outcomes while reducing the incidence of ovarian
hyperstimulation syndrome (OHSS) as compared to
Fixed Antagonist protocol. Hence, PPOS with MPA
seems to be a patient friendly and cost effective
choice for women undergoing ovarian stimulation
without reducing oocyte quality.
References:
1) Kuang Y, Chen Q, Fu Y et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone
surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015 Jul;104(1):62-70.e3.

41. Are There Differences in Euploidy Rates With
Oral DYD Primed Ovarian Stimulation Protocol
or the GnRH–ant Protocol?

42. DYD is a safe and efficacious treatment modality in freeze–all PGT–A cycles.
DYD: Dydrogesterone; GnRH–ant: Gonadotropin-releasing
hormone–antagonist; NGS: Next–generation sequencing; PGT–A:
Preimplantation genetic test–Aneuploidy.
Yang L, et al,. Reprod BioMed Online. 2022.
No. of cycles
A total of 780 cycles
were included; 390
cycles received
dydrogesterone and
390 cycles received
GnRH–ant.
Ovarian
responses
No significant
differences in the
baseline
characteristics and
ovarian responses
between two groups.
NGS testing
262 patients in the
DYD group and 263
patients in the
GnRH–ant group
received NGS testing.
Euploidy rates
No significant
differences between
the DYD and GnRH–
ant groups.

43. Safety of PPOS

44. SWOT analysis of PPOS protocols
Strengths Weaknesses
Opportunities Threats
Well tolerated
• low cost
• same number and quality of
oocytes
• same pregnancy rates (FET)
• No OHSS? (freeze all and agonist
trigger)
Few RCT
. Freeze & FET only
. Increased total dose of
gonadotrophins
more euploid blastocysts in poor
responders in one cycle (duostim)
. patient friendly (fewer
injections, easier scheduling or
random start)
change in current practice
. Need for a good
cryopreservation + FET NEEDE
. Obstetrical and perinatal outcomes:
limited data

45. Future Role Of PPOS
Reprod Biomed Online. 2019 Aug;39(2):321-331.

46. Future Role Of PPOS
Further studies are badly needed by all of us for
reproducibility
+
obstetric, pre-natal and long-term neonatal
outcomes, before this protocol can be
introduced on a wider scale

48. PROGESTERONE
PRIMED OVARIAN
DR. SHARDA JAIN
Stimulation In IVF