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Strategies for Improving
Success Rates in ART
DR SHALINI CHAWLA
PART - 2
Proprietary and confidential — do not distribute
Strategies for Improving
Success Rates in ART
• Tailoring Controlled Ovarian Stimulation
• Strategies for Luteal Phase in ART cycles
• Endometrial Receptivity Array
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The success of IVF depends on obtaining a sufficient number of eggs to create
high‐quality embryos for uterine transfer, without exposing the patient to the risks of
excessive ovarian stimulation 1
Ovarian stimulation (OS) is defined as pharmacological treatment with the intention of
inducing the development of ovarian follicles 2.
It can be used for two purposes:
(i) for timed intercourse or insemination and
(ii) in assisted reproduction, to obtain multiple oocytes at follicular aspiration.
Stimulation protocols
1. Macklon NS, The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocrine Reviews 2006;27:170‐207. 2. Zegers-
Hochschild F, The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 2017;32:1786–1801
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Ovarian Stimulation Protocols
Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69.
DHEA: Dehydroepiandrosterone; DOR: Diminished ovarian reserve; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; hCG: Human chorionic gonadotropin; HMG: Human menopausal gonadotropin; IU: International unit; IVF: In vitro
fertilization; rFSH: Recombinant follicle stimulating hormone; rLH: Recombinant luteinizing hormone.
1. High-dose
gonadotropins
(300–450 IU/day) HMG,
rFSH, rFSH + rLH, rFSH +
hCG (100–200 IU/day),
Luteal FSH start
3. Natural cycle or minimal stimulation
• Natural cycle
• Modified natural cycle (antagonist +
small dose of FSH)
• Minimal stimulation
(Letrozole/clomiphene + antagonist +
FSH)
2a. GnRH antagonist protocols
Fixed multiple dose
Flexible multiple dose
2b. GnRH agonist protocols
Short agonist, microdose flare,
ultra-short, long agonist
4. Adjuvants
Growth hormone,
DHEA, testosterone,
aspirin
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High-Dose Gonadotropins
1. Data on File (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69.
COS: Controlled ovarian stimulation; FSH: Follicle-stimulating hormone; hCG: Human chorionic gonadotropin; HMG: Human menopausal gonadotropin; IU: International unit; rLH: Recombinant luteinizing hormone.
Luteal start of FSH has been used to influence the recruitment of follicles without any reported clinical benefit.2
Ovarian COS protocols: Stimulation with high
doses of FSH (300–450 IU/day).2
The available evidence regarding addition of recombinant
LH to FSH is inconclusive.2
Low-dose hCG supplementation or addition of pure HMG
has shown some improvements in the oocyte yield.2
Poor oocyte quality
Patient discomfort
Gonadotropin associated
side effects
Drawbacks of high dose-
gonadotropins1
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GnRH Agonist and GnRH Antagonist Protocols
• Shorter duration of the analogue treatment
• Shorter duration of stimulation with FSH
• Lower risk of developing OHSS
• Lesser number of injections required
GnRH antagonists are, however,
associated with lower ongoing
pregnancy rates when compared to
long protocol agonists.
Long GnRH agonist treatment is perhaps
still the approach of choice.
Lambalk CB, et al. Hum Reprod Update. 2017;23(5):560–579.
FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; OHSS: Ovarian hyperstimulation syndrome; PCOS: Polycystic ovary syndrome.
Pituitary desensitization with prolonged
daily administration of a GnRH agonist
Long protocol
Preferred option in PCOS and
poor responders
An instant blockade of the pituitary
secretion with a GnRH antagonist
Short protocol
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GnRH Agonist Protocols
Pituitary desensitization with
prolonged daily administration of a
GnRH agonist
Long protocol
Long agonist protocol increases both duration of
treatment and total dose of gonadotropins necessary
to effect follicular development in poor responders.2
Short agonist protocol where agonist administration is
initiated in the early follicular phase before
gonadotropin administration is one of the most widely
used agonist protocols in poor responders.2
Agonists due to their initial flare effect may help in
recruitment of the follicles.2
Microdose flare and ultrashort protocols are preferred
by some clinicians, to minimize the pituitary
suppression, but have not shown to improve the clinical
outcomes.2
1.Data on file (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69.
FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; GnRHa: GnRH agonists.
GnRH agonist protocol1
Long agonist protocol increases both duration of
treatment and total dose of gonadotropins necessary to
effect follicular development in poor responders.2
Agonists due to their initial flare effect may help in
recruitment of the follicles.2
GnRH agonist protocol1
Proprietary and confidential — do not distribute 1.Data on file (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69.
GnRH Antagonist Protocols
Gonadotropin
GnRHantagonist
hCG OPU ET
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Single-dose regimen (French protocol)
hCG
GnRHantagonist
E2 >1000pg/mL
follicle 20mm
Gonadotropins
OPU ET
Menses
4
3
2
0
Multiple-dose protocol (Lubeck protocol)
Amp.
hMG
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
ET: Embryo transfer; hCG: Human chorionic gonadotropin; LH: Luteinizing
hormone; OPU: Ovum pick-up; GnRH: Gonadotropin releasing hormone.
Antagonists provide an effective way
of preventing premature LH surge
without prolonging the treatment
duration.
Pregnancy rates achieved are similar
to short agonist protocol.2
GnRH antagonist protocol1
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Natural/Minimal Stimulation:
Alternative to High-Dose FSH Protocols
1. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. 2. Data on file (1). Last accessed on 18 January 2021.
FSH: Follicle-stimulating hormone; IVF: In vitro fertilization; POR: Poor ovarian response.
Stimulation cycle types: Natural cycle IVF, modified natural cycle IVF(antagonists plus small doses of FSH), minimal
stimulation (letrozole or clomiphene citrate plus small doses of FSH plus antagonist)1
1
2
3
4
Abnormal follicular maturation
Premature ovulation of the single follicle
Failed fertilization
Failed oocyte retrieval, or empty follicle at retrieval
Natural/ minimal
stimulation is
associated with a
high risk of
cancellation due to
following reasons:2
Proprietary and confidential — do not distribute
• It is essential to be able to predict the response of the women to the hormones, to
choose the best protocol to produce a major number of follicles, which at the same
time allows the retrieval of a greater number of oocytes.
• Based on the response to standard stimulation regimens with stabilized doses of
gonadotropins, women can be classified into three classes:
Predicting Ovarian Response
Normal-responder
Poor-responder
High-responder
Pacchiarotti, Alessandro et al. “Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.” Current pharmaceutical
biotechnology vol. 17,4 (2016): 303-15.
Proprietary and confidential — do not distribute
A step towards personalized medicine:
Individualized COS (iCOS) determined by the use of biomarkers to test ovarian reserve
has the potential to optimize outcomes and reduce safety issues by adapting treatment
protocols according to each patient’s specific characteristics.
As new objective endocrine, paracrine, functional and/or genetic biomarkers of response
are developed, iCOS can be refined further still, and this will be a significant step towards
a personalised approach for IVF.
Individualized controlled ovarian stimulation
Bosch and Ezcurra. Individualised controlled ovarian stimulation (iCOS): maximising success rates for
assisted reproductive technology patients Reproductive Biology and Endocrinology 2011, 9:82
Proprietary and confidential — do not distribute
A Novel Tool in Identification of Low Prognosis Patients in ART
1. Esteves SC, et al. Front Endocrinol (Lausanne). 2018;9:461. 2. Conforti A, et al. Front Endocrinol (Lausanne). 2019;10:387.
AFC: Antral follicle count; AMH: Anti-Mullerian hormone; ART: Assisted reproductive treatment; IVF: In vitro fertilization; ng/mL: Nanogram per milliliter; OS: ovarian stimulation; POSEIDON: Patient-Oriented Strategies
Encompassing Individualize D Oocyte Number.
1. Age 3.
Ovarian biomarkers
(AMH and/or AFC)
No. oocytes retrieved
in previous OS cycle
<35
AFC<5
AMH <1.2ng/mL
<35
AFC≥5
AMH ≥1.2ng/mL
Subgroup a: <4
Subgroup b: 4–9
≥35
AFC<5
AMH <1.2ng/mL
≥35
AFC≥5
AMH ≥1.2ng/mL
Subgroup a: <4
Subgroup b: 4–9
2.
GROUP 1 GROUP 2
GROUP 3 GROUP 4
Advantages of Poseidon
criteria1
• Improves the ART
outcomes
• Promotes a patient-
tailored approach
• Maximizes IVF
success rates
Patient - Oriented Strategies Encompassing Individualized
Oocyte Number (POSEIDON)
Proprietary and confidential — do not distribute
Based on POSEIDON Criteria
What should be done if
ORT results are positive?
Best Practice in POSEIDON groups 1 and 2
Consider ART calculator and Genotype screening
Consider androgens in selected patients (in particular, POSEIDON group 2 with ovanan reserve
markers in the lower limits)
POSEIDON group 1 (Age <35) POSEIDON group 2 (Age ≥35)
POSEIDON group 2 (Age 35-
39)
Consider Duo-Stim approach
rLH 150 IU daily from stimulation day 1 in both
agonist and antagonist regimens
Recombiant FSH dose of 300 IU daily
Increase recombinant FSH dosage
• 50-75 IU if no variants
• 75-150 IU if FSH-R variants (maximum daily dose of 300
IU)
Consider adding rLH
2:1 ratio of rFSH and rLH from the first stimulation day in
women who consumed more than 3,000 IU or with a history
of follicular stagnation
Consider antagonist regimen, GnRHa trigger, and elective embyo freezing in cases of AFC >16 and/or AMH
>3.36 ng/mL
Consider preimplantation genetic testing for aneuploidy (PGT-A) in Poseidon group 2 (in particular, patients
aged >38)
Consider single blastocyst embryo trasfer
Pre-treatment
protocol
Stimulation
protocol
Trigger/Retrieval
Conforti A, et al. Front Endocrinol (Lausanne). 2019;10:387.
AFC: Antral follicle count; AMH: Anti-Mullerian hormone; ART: Assisted reproductive treatment; FSH: Follicle-stimulating hormone; GnRHa: Gonadotropin releasing hormone agonist; IU: International unit; IVF: In vitro fertilization;
POSEIDON: Patient-Oriented Strategies Encompassing Individualize D Oocyte Number. rLH: Recombinant luteinizing hormone; rFSH: Recombinant follicle-stimulating hormone; ng/mL: nanogram per milliliter.
Stimulation Protocols for low prognosis patients
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• The ‘short’, ‘ultrashort’, ‘micro-flare’ and ‘stop’ GnRH agonist protocols involve adjusting
the timing and dose of GnRH agonist administration, so that the patient benefits from the
initial flare-up of endogenous follicle stimulating hormone (FSH) and luteinizing
hormone (LH) that may ‘jump start’ the follicles, in addition to the action of exogenous
gonadotropins.
• Another modification to the standard long protocol involves changing the combination of
gonadotropins.
• For example, the addition of LH has been shown to improve cycle outcomes in poor
responders and patients > 35 years old.
• Moreover, pre-treatment with testosterone, estrogens or letrozole has also been proposed
to increase ovarian response in this particular population.
Bosch and Ezcurra. Individualised controlled ovarian stimulation (iCOS): maximising success rates for
assisted reproductive technology patients Reproductive Biology and Endocrinology 2011, 9:82
Adjusting the standard protocols for COS
Proprietary and confidential — do not distribute Durdag et al.Turk Ger Gynecol Assoc 2021
The efficacy of Dydrogesterone use to suppress premature luteinizing hormone surge on cycle
outcomes in controlled ovarian stimulation
• Dydrogesterone 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 GnRHant group
• 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.
Progesterone primed ovarian stimulation
Proprietary and confidential — do not distribute
Strategies for Improving
Success Rates in ART
• Tailoring Controlled Ovarian Stimulation
• Strategies for Luteal Phase in ART cycles
• Endometrial Receptivity Array
Proprietary and confidential — do not distribute
Treatment options for LPS in IVF
hCG
GnRHa: Gonadotropin releasing hormone agonist; hCG: Human chorionic gonadotropin; IVF: In vitro fertilization; OHSS: Ovarian hyperstimulation syndrome.
1. Karakaş Yılmaz N, et al. Turk J Obstet Gynecol. 2018;15(4):217–221. 2. Rashidi BH, et al. Asian Pac J Reprod. 2016; 5(6):490–494.
Standard approach
for IVF cycles1
OHSS
risk1
Premature endogenous
LH surge2
Proprietary and confidential — do not distribute 1. Griesinger G, et al. Hum Reprod. 2018;33(12):2212–2221.
2. Griesinger G, et al. Reprod Biomed Online. 2019;38(2):249–259.
Choosing the right progesterone
Oral micronized progesterone
Low bioavailability, adverse reactions such as
drowsiness, dizziness, and headache1
Intramuscular progesterone
Injection-site pain and abscesses1
Micronized vaginal progesterone
Associated with administration-related side effects,
such as vaginal irritation1
Oral dydrogesterone
Potent oral progestin with improved bioavailability1,2
Proprietary and confidential — do not distribute
Oral Dydrogesterone: Better and Convenient Option
Approved in threatened and recurrent miscarriage and other
progesterone deficiencies1
Greater bioavailability2
Effective at lower dose and causes endometrial
transformation2
Minimizes the activation of receptors other than progesterone
receptor, and thus minimizes unwanted effects2
Shifts cytokine balance from T-helper (Th)1 toward Th2 cytokine
production that is conducive to the success of pregnancy3
Suppression of T-cell and killer-cell activity6
Induces nitric oxide synthesis that improves endometrial
receptivity and pregnancy outcomes3,4
Increases progesterone-induced blocking factor production
thereby improving pregnancy success rates5
1. Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf. Last accessed on 25 January 2021. 2.
Schindler AE, et al. Maturitas. 2003;46(Suppl 1):S7–S16. 3. Raghupathy R, et al. Am J Reprod Immunol. 2015;74(5):419–426. 4. Abdel-Razik M, et al. J Reprod Infertil.
2014;15(3):142–146. 5. Kalinka J, et al. Am J Reprod Immunol. 2005;53(4):166–171. 6. Faust Z, et al. Am J Reprod Immunol. 1999;42(2):71–75.
Proprietary and confidential — for internal use
*Lotus I and Lotus II trials. †Total number of patients in all groups included in the study.
IVF, in vitro fertilization; LPS, luteal phase support; MVP, micronized vaginal progesterone
1. Tournaye H, Sukhikh GT, Kahler E, et al. Hum Reprod. 2017;32(5):1019-1027. 2. Griesinger G, Blockeel C, Sukhikh GT, et al. Human Reprod. 2018;33(12):2212-2221. 3. Vaisbuch E, Leong M, Shoham Z. Reprod Biomed Online.
2012;25:139-45. 4. Chakravarty BN, Shirazee HH, Dam P, et al. J Steroid Biochem Mol Biol. 2005;97:416-420. 5. Crinone 4% and 8% progesterone gel US Physician Information, June 2017. 6. Crinone 8% progesterone gel
Australian Product Information, 2 March 2011. 7. Utrogestan 200mg Australian Product Information, 12 July 2016. 8. Utrogestan vaginal 200 mg capsules. UK Public Assessment Report MHRA (Medicines and Healthcare
Products Regulatory Agency), October 2015. 9. Kleinstein J. Fertil Steril. 2005;83(6):1641-1649. 10. Progesterone 400 mg pessaries. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory
Agency), March 2017. 11. Doody KJ, Schnell VL, Foulk RA, et al. Fertil Steril. 2009;91(4):1012-1017. 12. Endometrin Australian Product Information, 19 September 2012. 13. Lockwood G, Griesinger G, Cometti B, et al. Fertil
Steril. 2014;101(1):112-119. 14. Baker VL, Jones CA, Doody K, et al. Hum Reprod. 2014;29(10):2212-2220. 15. Lubion 25 mg powder for solution for injection. Lubion 25 mg solution for injection. UK Public Assessment Report
MHRA.
Dydrogesterone is an effective and well tolerated oral
option for LPS in IVF1,2
MVP was used in almost two thirds of IVF
cycles worldwide,3 but is associated
with administration-related side effects
as well as less patient acceptance4
Oral dydrogesterone was evaluated
in two large randomized controlled trials and
was found to be at least equivalent to MVP for
pregnancy rate and live birth rate1,2 Oral
dydrogesterone
Lotus Program*1,2
238
430
768
1211
1483
2065
Number of patients in registration trials†
Subcutaneous
progesterone
injection13-15
MVP
insert11-12
Progesterone
pessary10
MVP
gel 8%5-6
MVP
capsule7-9
*At 12 weeks of gestation. MVP, micronized vaginal progesterone
1. Tournaye H, Sukhikh GT, Kahler E, et al. Hum Reprod. 2017;32(5):1019-1027.
2. Griesinger G, Blockeel C, Sukhikh GT, et al. Human Reprod. 2018;33(12):2212-2221.
Dydrogesterone achieves non-inferior pregnancy rates
versus MVP capsule or gel at 12 weeks of gestation
Dydrogesterone
30 mg/day
37.6
33.1
0
5
10
15
20
25
30
35
40
MVP capsule
600 mg/day
(187/497)
(158/477)
Dydrogesterone
30 mg/day
38.7
35.0
0
5
10
15
20
25
30
35
40
MVP gel
90 mg/day
(191/494)
(171/489)
Pregnancy
rate
(%)
Pregnancy
rate
(%)
LOTUS I1
Pregnancy rate*1,2
LOTUS II2
Proprietary and confidential — do not distribute Griesinger G. PLoS One. 2020;15(11):e0241044.
Key Findings of Griesinger et al.
Systematic Review & Meta-analysis of Individual Participant Data
Significantly higher pregnancy
rate than MVP capsules and gels.
Significantly higher live birth
rate than MVP capsules and
gels.
Well-established safety profile
with no significant maternal or
fetal safety concerns.
Oral dydrogesterone was associated with
MVP: Micronized vaginal progesterone.
Proprietary and confidential — do not distribute
Dydrogesterone for Luteal Phase Support in Programmed FET cycles
Pabuccu et al. conducted a pilot RCT to compare three different routes of progesterone administration in artificially
programmed FET cycles
Outcomes
Treatment with 40 mg/day oral DYD, 180 mg/day progesterone vaginal gel, or 100 mg/day IMP revealed
similar reproductive outcomes in programmed FET cycles.
Oral administration is better tolerated and showed a lower side effect profile per patient when compared
with the other arms
Pabuccu E, et. al. Oral, vaginal or intramuscular progesterone in programmed frozen embryo transfer cycles: A pilot randomized
controlled trial. Reprod. Biomed. Online. 2022
Oral dydrogesterone (20mg BD)
(n = 52)
Progesterone Vaginal Gel 8% (90mg BD)
(n = 55)
Intramuscular progesterone 50 mg/ml in oil BD
(n = 44)
Oral dydrogesterone (20mg BD)
(n = 52)
Intramuscular progesterone 50 mg/ml in oil BD
(n = 44)
Oral dydrogesterone (20mg BD)
(n = 52)
Intramuscular progesterone 50 mg/ml in oil BD
(n = 44)
Proprietary and confidential — do not distribute
Individualized luteal phase support using additional oral dydrogesterone in
artificially prepared frozen embryo transfer cycles
Mackens et al.
Rescue strategy when low serum progesterone
concentrations are detected at the moment
of FET in HRT cycles
Micronized Vaginal Progesterone (MVP) - 400 mg twice daily
Serum progesterone concentrations were assessed prior to
FET
147 Patients with low serum progesterone (<8.8 ng/ml)
Received additional oral dydrogesterone supplementation
(10 mg three times daily) from the day after FET onwards
ONGOING PREGNANCY RATE
(p=0.85b)
LIVE BIRTH RATE
(p=0.84b)
Additional oral dydrogesterone supplementation in this context gives rise to comparable live birth rate in
patients with low serum progesterone as observed in patients with normal progesterone concentrations
Mackens S, Pais F, Drakopoulos P et al. Individualized luteal phase support using additional oral dydrogesterone in artificially prepared frozen
embryo transfer cycles: is it beneficial? Reprod Biomed Online. 2023;46(6):939-945
Luteal Phase Support:
Proprietary and confidential — do not distribute
Strategies for Improving
Success Rates in ART
• Tailoring Controlled Ovarian Stimulation
• Strategies for Luteal Phase in ART cycles
• Endometrial Receptivity Array
Proprietary and confidential — do not distribute
ERA is a test, which analyze the 238 genes in an endometrial tissue sample obtained by biopsy during a specific
interval in the menstrual cycle2, which has a sensitivity and specificity of 0.99758 and 0.88573, respectively.
Endometrial receptivity array (ERA)
1. Kliman H.J., Frankfurter D. Clinical approach to recurrent implantation failure: Evidence-based evaluation of the endometrium. Fertil. Steril. 2019;111:618–
628. 2. Miravet-Valenciano JA, Understanding and improving endometrialreceptivity. Curr Opin Obstet Gynecol 2015;27: 187–92, 2. Huy Phuong Tran, The impact of an endometrial receptivity
array on personalizing embryo transfer for patients with infertility: a meta-analysis, Vol 3, Issue 3, 2022
Suggests a suitable time for embryo
transfer
Indicates prereceptive or postreceptive moment,
which is not ideal for embryo transfer
After ERA confirms the precise WOI timing, the embryo is
transferred in the subsequent cycle3
Outcome
The endometrial receptivity array (ERA) was first developed in 2011 by Díaz-Gimeno et al1.
Receptive Non
receptive
Proprietary and confidential — do not distribute
• By using FET, the embryos are frozen for use in subsequent cycles, thus avoiding
supraphysiologic hormone levels and an asynchronous implantation window,
leading to better outcomes than those seen in fresh transfers.
• The ERA can be used in a modified nFET cycle in an attempt to better guide the
timing of embryo transfer to best match the WOI.
• Administration of hCG is necessary in order to time embryo transfer to when the
endometrium is most receptive.
• The biopsy is taken at either LH +7 or hCG +7, which are considered to be equal
under the ERA protocol, and sent to Igenomix, the medical laboratory that analyzes
the ERA
FET- Fresh embryo transfer
ERA in the Context of Natural Frozen Embryo Transfer
Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A
Personalized Approach to Embryo Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749
Proprietary and confidential — do not distribute
ERA in the Context of Hormone Replacement Therapy
Frozen Embryo Transfer
In using an ERA to guide the timing for an HRT-FET cycle, a
patient will ultimately need two cycles, the first being an ERA
cycle, and the second being an HRT-FET cycle.
In the ERA cycle, the patient uses the same medications they
would in an HRT-FET cycle, mimicking the uterine conditions
in an eventual transfer cycle
Endometrial biopsy can be performed on day P +5.Then the
ERA results are used to personalize the date of the embryo
transfer to the individual receptivity of each patient’s
endometrium
Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A Personalized
Approach to Embryo Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749
Proprietary and confidential — do not distribute
• There is an increased percentage of WOI displacement in RIF patients, therefore
leading to the incorporation of the ERA in personalized frozen embryo transfer (pET)
as a therapeutic strategy.
• Multiple studies1,2,3 showed that when pET was employed in specifically RIF patients
with a nonreceptive endometrium, the implantation rate and pregnancy rate increased
to the level of that of receptive RIF patients
• A retrospective cohort study, performed in 2015 at a fertility center in India,
demonstrates this as well1.
• Another study concluded that the ERA is a tool that is beneficial in RIF patients,
increasing implantation and pregnancy rates to levels that are comparable to those of
a non-RIF population4,5
Clinical outcomes using ERA in
Recurrent Implantation Failure (RIF)
1. Mahajan N. Endometrial receptivity array: Clinical application. J. Hum. Reprod. Sci. 2015;8:121–129. 2. Tan J. The role of the (ERA) in patients who have failed euploid embryo transfers. J. Assist. Reprod. Genet. 2018;35:683–692, 3. Kaur S., Naidu P. Why results of
endometrial receptivity assay testing should not be discounted in recurrent implantation failure? Onco Fertil. J. 2019, 4. Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A Personalized Approach to Embryo
Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749, 5. Rose B.I. On the utility of the endometrial receptivity assay (era) to correct recurrent implantation failure (rif): Not as simple as it seems. Fertil. Steril. 2020;114:e168.
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Strategies for Improving Success Rates in ART PART

  • 1. Proprietary and confidential — do not distribute Strategies for Improving Success Rates in ART DR SHALINI CHAWLA PART - 2
  • 2. Proprietary and confidential — do not distribute Strategies for Improving Success Rates in ART • Tailoring Controlled Ovarian Stimulation • Strategies for Luteal Phase in ART cycles • Endometrial Receptivity Array
  • 3. Proprietary and confidential — do not distribute The success of IVF depends on obtaining a sufficient number of eggs to create high‐quality embryos for uterine transfer, without exposing the patient to the risks of excessive ovarian stimulation 1 Ovarian stimulation (OS) is defined as pharmacological treatment with the intention of inducing the development of ovarian follicles 2. It can be used for two purposes: (i) for timed intercourse or insemination and (ii) in assisted reproduction, to obtain multiple oocytes at follicular aspiration. Stimulation protocols 1. Macklon NS, The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocrine Reviews 2006;27:170‐207. 2. Zegers- Hochschild F, The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 2017;32:1786–1801
  • 4. Proprietary and confidential — do not distribute Ovarian Stimulation Protocols Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. DHEA: Dehydroepiandrosterone; DOR: Diminished ovarian reserve; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; hCG: Human chorionic gonadotropin; HMG: Human menopausal gonadotropin; IU: International unit; IVF: In vitro fertilization; rFSH: Recombinant follicle stimulating hormone; rLH: Recombinant luteinizing hormone. 1. High-dose gonadotropins (300–450 IU/day) HMG, rFSH, rFSH + rLH, rFSH + hCG (100–200 IU/day), Luteal FSH start 3. Natural cycle or minimal stimulation • Natural cycle • Modified natural cycle (antagonist + small dose of FSH) • Minimal stimulation (Letrozole/clomiphene + antagonist + FSH) 2a. GnRH antagonist protocols Fixed multiple dose Flexible multiple dose 2b. GnRH agonist protocols Short agonist, microdose flare, ultra-short, long agonist 4. Adjuvants Growth hormone, DHEA, testosterone, aspirin
  • 5. Proprietary and confidential — do not distribute High-Dose Gonadotropins 1. Data on File (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. COS: Controlled ovarian stimulation; FSH: Follicle-stimulating hormone; hCG: Human chorionic gonadotropin; HMG: Human menopausal gonadotropin; IU: International unit; rLH: Recombinant luteinizing hormone. Luteal start of FSH has been used to influence the recruitment of follicles without any reported clinical benefit.2 Ovarian COS protocols: Stimulation with high doses of FSH (300–450 IU/day).2 The available evidence regarding addition of recombinant LH to FSH is inconclusive.2 Low-dose hCG supplementation or addition of pure HMG has shown some improvements in the oocyte yield.2 Poor oocyte quality Patient discomfort Gonadotropin associated side effects Drawbacks of high dose- gonadotropins1
  • 6. Proprietary and confidential — do not distribute GnRH Agonist and GnRH Antagonist Protocols • Shorter duration of the analogue treatment • Shorter duration of stimulation with FSH • Lower risk of developing OHSS • Lesser number of injections required GnRH antagonists are, however, associated with lower ongoing pregnancy rates when compared to long protocol agonists. Long GnRH agonist treatment is perhaps still the approach of choice. Lambalk CB, et al. Hum Reprod Update. 2017;23(5):560–579. FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; OHSS: Ovarian hyperstimulation syndrome; PCOS: Polycystic ovary syndrome. Pituitary desensitization with prolonged daily administration of a GnRH agonist Long protocol Preferred option in PCOS and poor responders An instant blockade of the pituitary secretion with a GnRH antagonist Short protocol
  • 7. Proprietary and confidential — do not distribute GnRH Agonist Protocols Pituitary desensitization with prolonged daily administration of a GnRH agonist Long protocol Long agonist protocol increases both duration of treatment and total dose of gonadotropins necessary to effect follicular development in poor responders.2 Short agonist protocol where agonist administration is initiated in the early follicular phase before gonadotropin administration is one of the most widely used agonist protocols in poor responders.2 Agonists due to their initial flare effect may help in recruitment of the follicles.2 Microdose flare and ultrashort protocols are preferred by some clinicians, to minimize the pituitary suppression, but have not shown to improve the clinical outcomes.2 1.Data on file (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. FSH: Follicle-stimulating hormone; GnRH: Gonadotropin releasing hormone; GnRHa: GnRH agonists. GnRH agonist protocol1 Long agonist protocol increases both duration of treatment and total dose of gonadotropins necessary to effect follicular development in poor responders.2 Agonists due to their initial flare effect may help in recruitment of the follicles.2 GnRH agonist protocol1
  • 8. Proprietary and confidential — do not distribute 1.Data on file (1). Last accessed on 18 January 2021. 2. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. GnRH Antagonist Protocols Gonadotropin GnRHantagonist hCG OPU ET 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Single-dose regimen (French protocol) hCG GnRHantagonist E2 >1000pg/mL follicle 20mm Gonadotropins OPU ET Menses 4 3 2 0 Multiple-dose protocol (Lubeck protocol) Amp. hMG 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 ET: Embryo transfer; hCG: Human chorionic gonadotropin; LH: Luteinizing hormone; OPU: Ovum pick-up; GnRH: Gonadotropin releasing hormone. Antagonists provide an effective way of preventing premature LH surge without prolonging the treatment duration. Pregnancy rates achieved are similar to short agonist protocol.2 GnRH antagonist protocol1
  • 9. Proprietary and confidential — do not distribute Natural/Minimal Stimulation: Alternative to High-Dose FSH Protocols 1. Jirge PR. J Hum Reprod Sci. 2016;9(2):63–69. 2. Data on file (1). Last accessed on 18 January 2021. FSH: Follicle-stimulating hormone; IVF: In vitro fertilization; POR: Poor ovarian response. Stimulation cycle types: Natural cycle IVF, modified natural cycle IVF(antagonists plus small doses of FSH), minimal stimulation (letrozole or clomiphene citrate plus small doses of FSH plus antagonist)1 1 2 3 4 Abnormal follicular maturation Premature ovulation of the single follicle Failed fertilization Failed oocyte retrieval, or empty follicle at retrieval Natural/ minimal stimulation is associated with a high risk of cancellation due to following reasons:2
  • 10. Proprietary and confidential — do not distribute • It is essential to be able to predict the response of the women to the hormones, to choose the best protocol to produce a major number of follicles, which at the same time allows the retrieval of a greater number of oocytes. • Based on the response to standard stimulation regimens with stabilized doses of gonadotropins, women can be classified into three classes: Predicting Ovarian Response Normal-responder Poor-responder High-responder Pacchiarotti, Alessandro et al. “Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.” Current pharmaceutical biotechnology vol. 17,4 (2016): 303-15.
  • 11. Proprietary and confidential — do not distribute A step towards personalized medicine: Individualized COS (iCOS) determined by the use of biomarkers to test ovarian reserve has the potential to optimize outcomes and reduce safety issues by adapting treatment protocols according to each patient’s specific characteristics. As new objective endocrine, paracrine, functional and/or genetic biomarkers of response are developed, iCOS can be refined further still, and this will be a significant step towards a personalised approach for IVF. Individualized controlled ovarian stimulation Bosch and Ezcurra. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients Reproductive Biology and Endocrinology 2011, 9:82
  • 12. Proprietary and confidential — do not distribute A Novel Tool in Identification of Low Prognosis Patients in ART 1. Esteves SC, et al. Front Endocrinol (Lausanne). 2018;9:461. 2. Conforti A, et al. Front Endocrinol (Lausanne). 2019;10:387. AFC: Antral follicle count; AMH: Anti-Mullerian hormone; ART: Assisted reproductive treatment; IVF: In vitro fertilization; ng/mL: Nanogram per milliliter; OS: ovarian stimulation; POSEIDON: Patient-Oriented Strategies Encompassing Individualize D Oocyte Number. 1. Age 3. Ovarian biomarkers (AMH and/or AFC) No. oocytes retrieved in previous OS cycle <35 AFC<5 AMH <1.2ng/mL <35 AFC≥5 AMH ≥1.2ng/mL Subgroup a: <4 Subgroup b: 4–9 ≥35 AFC<5 AMH <1.2ng/mL ≥35 AFC≥5 AMH ≥1.2ng/mL Subgroup a: <4 Subgroup b: 4–9 2. GROUP 1 GROUP 2 GROUP 3 GROUP 4 Advantages of Poseidon criteria1 • Improves the ART outcomes • Promotes a patient- tailored approach • Maximizes IVF success rates Patient - Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON)
  • 13. Proprietary and confidential — do not distribute Based on POSEIDON Criteria What should be done if ORT results are positive? Best Practice in POSEIDON groups 1 and 2 Consider ART calculator and Genotype screening Consider androgens in selected patients (in particular, POSEIDON group 2 with ovanan reserve markers in the lower limits) POSEIDON group 1 (Age <35) POSEIDON group 2 (Age ≥35) POSEIDON group 2 (Age 35- 39) Consider Duo-Stim approach rLH 150 IU daily from stimulation day 1 in both agonist and antagonist regimens Recombiant FSH dose of 300 IU daily Increase recombinant FSH dosage • 50-75 IU if no variants • 75-150 IU if FSH-R variants (maximum daily dose of 300 IU) Consider adding rLH 2:1 ratio of rFSH and rLH from the first stimulation day in women who consumed more than 3,000 IU or with a history of follicular stagnation Consider antagonist regimen, GnRHa trigger, and elective embyo freezing in cases of AFC >16 and/or AMH >3.36 ng/mL Consider preimplantation genetic testing for aneuploidy (PGT-A) in Poseidon group 2 (in particular, patients aged >38) Consider single blastocyst embryo trasfer Pre-treatment protocol Stimulation protocol Trigger/Retrieval Conforti A, et al. Front Endocrinol (Lausanne). 2019;10:387. AFC: Antral follicle count; AMH: Anti-Mullerian hormone; ART: Assisted reproductive treatment; FSH: Follicle-stimulating hormone; GnRHa: Gonadotropin releasing hormone agonist; IU: International unit; IVF: In vitro fertilization; POSEIDON: Patient-Oriented Strategies Encompassing Individualize D Oocyte Number. rLH: Recombinant luteinizing hormone; rFSH: Recombinant follicle-stimulating hormone; ng/mL: nanogram per milliliter. Stimulation Protocols for low prognosis patients
  • 14. Proprietary and confidential — do not distribute • The ‘short’, ‘ultrashort’, ‘micro-flare’ and ‘stop’ GnRH agonist protocols involve adjusting the timing and dose of GnRH agonist administration, so that the patient benefits from the initial flare-up of endogenous follicle stimulating hormone (FSH) and luteinizing hormone (LH) that may ‘jump start’ the follicles, in addition to the action of exogenous gonadotropins. • Another modification to the standard long protocol involves changing the combination of gonadotropins. • For example, the addition of LH has been shown to improve cycle outcomes in poor responders and patients > 35 years old. • Moreover, pre-treatment with testosterone, estrogens or letrozole has also been proposed to increase ovarian response in this particular population. Bosch and Ezcurra. Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients Reproductive Biology and Endocrinology 2011, 9:82 Adjusting the standard protocols for COS
  • 15. Proprietary and confidential — do not distribute Durdag et al.Turk Ger Gynecol Assoc 2021 The efficacy of Dydrogesterone use to suppress premature luteinizing hormone surge on cycle outcomes in controlled ovarian stimulation • Dydrogesterone 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 GnRHant group • 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. Progesterone primed ovarian stimulation
  • 16. Proprietary and confidential — do not distribute Strategies for Improving Success Rates in ART • Tailoring Controlled Ovarian Stimulation • Strategies for Luteal Phase in ART cycles • Endometrial Receptivity Array
  • 17. Proprietary and confidential — do not distribute Treatment options for LPS in IVF hCG GnRHa: Gonadotropin releasing hormone agonist; hCG: Human chorionic gonadotropin; IVF: In vitro fertilization; OHSS: Ovarian hyperstimulation syndrome. 1. Karakaş Yılmaz N, et al. Turk J Obstet Gynecol. 2018;15(4):217–221. 2. Rashidi BH, et al. Asian Pac J Reprod. 2016; 5(6):490–494. Standard approach for IVF cycles1 OHSS risk1 Premature endogenous LH surge2
  • 18. Proprietary and confidential — do not distribute 1. Griesinger G, et al. Hum Reprod. 2018;33(12):2212–2221. 2. Griesinger G, et al. Reprod Biomed Online. 2019;38(2):249–259. Choosing the right progesterone Oral micronized progesterone Low bioavailability, adverse reactions such as drowsiness, dizziness, and headache1 Intramuscular progesterone Injection-site pain and abscesses1 Micronized vaginal progesterone Associated with administration-related side effects, such as vaginal irritation1 Oral dydrogesterone Potent oral progestin with improved bioavailability1,2
  • 19. Proprietary and confidential — do not distribute Oral Dydrogesterone: Better and Convenient Option Approved in threatened and recurrent miscarriage and other progesterone deficiencies1 Greater bioavailability2 Effective at lower dose and causes endometrial transformation2 Minimizes the activation of receptors other than progesterone receptor, and thus minimizes unwanted effects2 Shifts cytokine balance from T-helper (Th)1 toward Th2 cytokine production that is conducive to the success of pregnancy3 Suppression of T-cell and killer-cell activity6 Induces nitric oxide synthesis that improves endometrial receptivity and pregnancy outcomes3,4 Increases progesterone-induced blocking factor production thereby improving pregnancy success rates5 1. Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf. Last accessed on 25 January 2021. 2. Schindler AE, et al. Maturitas. 2003;46(Suppl 1):S7–S16. 3. Raghupathy R, et al. Am J Reprod Immunol. 2015;74(5):419–426. 4. Abdel-Razik M, et al. J Reprod Infertil. 2014;15(3):142–146. 5. Kalinka J, et al. Am J Reprod Immunol. 2005;53(4):166–171. 6. Faust Z, et al. Am J Reprod Immunol. 1999;42(2):71–75.
  • 20. Proprietary and confidential — for internal use *Lotus I and Lotus II trials. †Total number of patients in all groups included in the study. IVF, in vitro fertilization; LPS, luteal phase support; MVP, micronized vaginal progesterone 1. Tournaye H, Sukhikh GT, Kahler E, et al. Hum Reprod. 2017;32(5):1019-1027. 2. Griesinger G, Blockeel C, Sukhikh GT, et al. Human Reprod. 2018;33(12):2212-2221. 3. Vaisbuch E, Leong M, Shoham Z. Reprod Biomed Online. 2012;25:139-45. 4. Chakravarty BN, Shirazee HH, Dam P, et al. J Steroid Biochem Mol Biol. 2005;97:416-420. 5. Crinone 4% and 8% progesterone gel US Physician Information, June 2017. 6. Crinone 8% progesterone gel Australian Product Information, 2 March 2011. 7. Utrogestan 200mg Australian Product Information, 12 July 2016. 8. Utrogestan vaginal 200 mg capsules. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory Agency), October 2015. 9. Kleinstein J. Fertil Steril. 2005;83(6):1641-1649. 10. Progesterone 400 mg pessaries. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory Agency), March 2017. 11. Doody KJ, Schnell VL, Foulk RA, et al. Fertil Steril. 2009;91(4):1012-1017. 12. Endometrin Australian Product Information, 19 September 2012. 13. Lockwood G, Griesinger G, Cometti B, et al. Fertil Steril. 2014;101(1):112-119. 14. Baker VL, Jones CA, Doody K, et al. Hum Reprod. 2014;29(10):2212-2220. 15. Lubion 25 mg powder for solution for injection. Lubion 25 mg solution for injection. UK Public Assessment Report MHRA. Dydrogesterone is an effective and well tolerated oral option for LPS in IVF1,2 MVP was used in almost two thirds of IVF cycles worldwide,3 but is associated with administration-related side effects as well as less patient acceptance4 Oral dydrogesterone was evaluated in two large randomized controlled trials and was found to be at least equivalent to MVP for pregnancy rate and live birth rate1,2 Oral dydrogesterone Lotus Program*1,2 238 430 768 1211 1483 2065 Number of patients in registration trials† Subcutaneous progesterone injection13-15 MVP insert11-12 Progesterone pessary10 MVP gel 8%5-6 MVP capsule7-9
  • 21. *At 12 weeks of gestation. MVP, micronized vaginal progesterone 1. Tournaye H, Sukhikh GT, Kahler E, et al. Hum Reprod. 2017;32(5):1019-1027. 2. Griesinger G, Blockeel C, Sukhikh GT, et al. Human Reprod. 2018;33(12):2212-2221. Dydrogesterone achieves non-inferior pregnancy rates versus MVP capsule or gel at 12 weeks of gestation Dydrogesterone 30 mg/day 37.6 33.1 0 5 10 15 20 25 30 35 40 MVP capsule 600 mg/day (187/497) (158/477) Dydrogesterone 30 mg/day 38.7 35.0 0 5 10 15 20 25 30 35 40 MVP gel 90 mg/day (191/494) (171/489) Pregnancy rate (%) Pregnancy rate (%) LOTUS I1 Pregnancy rate*1,2 LOTUS II2
  • 22. Proprietary and confidential — do not distribute Griesinger G. PLoS One. 2020;15(11):e0241044. Key Findings of Griesinger et al. Systematic Review & Meta-analysis of Individual Participant Data Significantly higher pregnancy rate than MVP capsules and gels. Significantly higher live birth rate than MVP capsules and gels. Well-established safety profile with no significant maternal or fetal safety concerns. Oral dydrogesterone was associated with MVP: Micronized vaginal progesterone.
  • 23. Proprietary and confidential — do not distribute Dydrogesterone for Luteal Phase Support in Programmed FET cycles Pabuccu et al. conducted a pilot RCT to compare three different routes of progesterone administration in artificially programmed FET cycles Outcomes Treatment with 40 mg/day oral DYD, 180 mg/day progesterone vaginal gel, or 100 mg/day IMP revealed similar reproductive outcomes in programmed FET cycles. Oral administration is better tolerated and showed a lower side effect profile per patient when compared with the other arms Pabuccu E, et. al. Oral, vaginal or intramuscular progesterone in programmed frozen embryo transfer cycles: A pilot randomized controlled trial. Reprod. Biomed. Online. 2022 Oral dydrogesterone (20mg BD) (n = 52) Progesterone Vaginal Gel 8% (90mg BD) (n = 55) Intramuscular progesterone 50 mg/ml in oil BD (n = 44) Oral dydrogesterone (20mg BD) (n = 52) Intramuscular progesterone 50 mg/ml in oil BD (n = 44) Oral dydrogesterone (20mg BD) (n = 52) Intramuscular progesterone 50 mg/ml in oil BD (n = 44)
  • 24. Proprietary and confidential — do not distribute Individualized luteal phase support using additional oral dydrogesterone in artificially prepared frozen embryo transfer cycles Mackens et al. Rescue strategy when low serum progesterone concentrations are detected at the moment of FET in HRT cycles Micronized Vaginal Progesterone (MVP) - 400 mg twice daily Serum progesterone concentrations were assessed prior to FET 147 Patients with low serum progesterone (<8.8 ng/ml) Received additional oral dydrogesterone supplementation (10 mg three times daily) from the day after FET onwards ONGOING PREGNANCY RATE (p=0.85b) LIVE BIRTH RATE (p=0.84b) Additional oral dydrogesterone supplementation in this context gives rise to comparable live birth rate in patients with low serum progesterone as observed in patients with normal progesterone concentrations Mackens S, Pais F, Drakopoulos P et al. Individualized luteal phase support using additional oral dydrogesterone in artificially prepared frozen embryo transfer cycles: is it beneficial? Reprod Biomed Online. 2023;46(6):939-945 Luteal Phase Support:
  • 25. Proprietary and confidential — do not distribute Strategies for Improving Success Rates in ART • Tailoring Controlled Ovarian Stimulation • Strategies for Luteal Phase in ART cycles • Endometrial Receptivity Array
  • 26. Proprietary and confidential — do not distribute ERA is a test, which analyze the 238 genes in an endometrial tissue sample obtained by biopsy during a specific interval in the menstrual cycle2, which has a sensitivity and specificity of 0.99758 and 0.88573, respectively. Endometrial receptivity array (ERA) 1. Kliman H.J., Frankfurter D. Clinical approach to recurrent implantation failure: Evidence-based evaluation of the endometrium. Fertil. Steril. 2019;111:618– 628. 2. Miravet-Valenciano JA, Understanding and improving endometrialreceptivity. Curr Opin Obstet Gynecol 2015;27: 187–92, 2. Huy Phuong Tran, The impact of an endometrial receptivity array on personalizing embryo transfer for patients with infertility: a meta-analysis, Vol 3, Issue 3, 2022 Suggests a suitable time for embryo transfer Indicates prereceptive or postreceptive moment, which is not ideal for embryo transfer After ERA confirms the precise WOI timing, the embryo is transferred in the subsequent cycle3 Outcome The endometrial receptivity array (ERA) was first developed in 2011 by Díaz-Gimeno et al1. Receptive Non receptive
  • 27. Proprietary and confidential — do not distribute • By using FET, the embryos are frozen for use in subsequent cycles, thus avoiding supraphysiologic hormone levels and an asynchronous implantation window, leading to better outcomes than those seen in fresh transfers. • The ERA can be used in a modified nFET cycle in an attempt to better guide the timing of embryo transfer to best match the WOI. • Administration of hCG is necessary in order to time embryo transfer to when the endometrium is most receptive. • The biopsy is taken at either LH +7 or hCG +7, which are considered to be equal under the ERA protocol, and sent to Igenomix, the medical laboratory that analyzes the ERA FET- Fresh embryo transfer ERA in the Context of Natural Frozen Embryo Transfer Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A Personalized Approach to Embryo Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749
  • 28. Proprietary and confidential — do not distribute ERA in the Context of Hormone Replacement Therapy Frozen Embryo Transfer In using an ERA to guide the timing for an HRT-FET cycle, a patient will ultimately need two cycles, the first being an ERA cycle, and the second being an HRT-FET cycle. In the ERA cycle, the patient uses the same medications they would in an HRT-FET cycle, mimicking the uterine conditions in an eventual transfer cycle Endometrial biopsy can be performed on day P +5.Then the ERA results are used to personalize the date of the embryo transfer to the individual receptivity of each patient’s endometrium Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A Personalized Approach to Embryo Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749
  • 29. Proprietary and confidential — do not distribute • There is an increased percentage of WOI displacement in RIF patients, therefore leading to the incorporation of the ERA in personalized frozen embryo transfer (pET) as a therapeutic strategy. • Multiple studies1,2,3 showed that when pET was employed in specifically RIF patients with a nonreceptive endometrium, the implantation rate and pregnancy rate increased to the level of that of receptive RIF patients • A retrospective cohort study, performed in 2015 at a fertility center in India, demonstrates this as well1. • Another study concluded that the ERA is a tool that is beneficial in RIF patients, increasing implantation and pregnancy rates to levels that are comparable to those of a non-RIF population4,5 Clinical outcomes using ERA in Recurrent Implantation Failure (RIF) 1. Mahajan N. Endometrial receptivity array: Clinical application. J. Hum. Reprod. Sci. 2015;8:121–129. 2. Tan J. The role of the (ERA) in patients who have failed euploid embryo transfers. J. Assist. Reprod. Genet. 2018;35:683–692, 3. Kaur S., Naidu P. Why results of endometrial receptivity assay testing should not be discounted in recurrent implantation failure? Onco Fertil. J. 2019, 4. Rubin SC, Abdulkadir M, Lewis J, Harutyunyan A, Hirani R, Grimes CL. Review of Endometrial Receptivity Array: A Personalized Approach to Embryo Transfer and Its Clinical Applications. J Pers Med. 2023 Apr 27;13(5):749, 5. Rose B.I. On the utility of the endometrial receptivity assay (era) to correct recurrent implantation failure (rif): Not as simple as it seems. Fertil. Steril. 2020;114:e168.
  • 30. Proprietary and confidential — do not distribute 26-Mar-24 Enter title via "insert>header and footer>footer" | | 30

Editor's Notes

  1. Various treatment regimens for management of patients with diminished ovarian reserve (DOR) are as follows: High dose gonadotropins (300–450 International unit (IU)/day): Human menopausal gonadotropin (HMG), human recombinant follicle stimulating hormone (rFSH), rFSH + recombinant luteinizing hormone (rLH), rFSH + human chorionic gonadotropin (hCG) (100–200IU/day), luteal FSH start 2a. GnRH antagonist protocols Fixed multiple dose, flexible multiple dose 2b. Gonadotropin releasing hormone (GnRH) agonist protocols Short agonist, microdose flare, ultra-short, long agonist 3. Natural cycle or minimal stimulation in vitro fertilization (IVF) Natural cycle, modified natural cycle (antagonist + small dose of FSH), Minimal stimulation (Letrozole/clomiphene + antagonist + FSH) 4. Adjuvants Growth hormone, dehydroepiandrosterone (DHEA), testosterone, aspirin Reference Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–69.
  2. High doses of gonadotropins may not benefit the patient beyond a particular dose and may also increase the possibility of poor oocyte quality, patient discomfort, and side effects.1 Most widely used ovarian controlled ovarian stimulation (COS) protocols in poor responders involve stimulation with high doses of follicle-stimulating hormone (FSH) (300–450 IU/day) to maximize the oocyte yield.2 The addition of luteinizing hormone (LH) in the early follicular phase may have beneficial effect on the oocyte and hence embryo quality.2 However, the available evidence regarding addition of recombinant LH to FSH is inconclusive.2 Low-dose hCG supplementation or addition of pure HMG where hCG is the source of LH activity has shown some improvements in the oocyte yield. 2 Luteal start of FSH has been used to influence the recruitment of follicles without any reported clinical benefit. 2 References Data on File (1). Last accessed on 18 January 2021. Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–69.
  3. The agonist or long protocol involves pituitary desensitization with prolonged daily administration of a gonadotropin releasing hormone (GnRH), while the antagonist protocol or short protocol involves in instant blockade of the pituitary luteinizing hormone (LH) secretion with a GnRH antagonist. Both procedures are effective in blocking premature LH surges. Advantages of antagonists or short protocol: Shorter duration of the analogue treatment Shorter duration of stimulation with follicle-stimulating hormone (FSH) Lower risk of developing ovarian hyperstimulation syndrome (OHSS) Apart from the above advantages, with the standard ‘long agonist protocol’ around 25 daily subcutaneous injections are needed, whereas antagonists require around five daily subcutaneous injections. GnRH antagonists are, however, associated with lower ongoing pregnancy rates when compared to long protocol agonists. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with polycystic ovary syndrome (PCOS) and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and, therefore, could be considered as standard treatment. Reference Lambalk CB, Banga FR, Huirne JA, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update. 2017;23(5):560–579.
  4. The agonist protocols, according to Indian Society for Assisted Reproduction (ISAR ), have been shown on the screen.1 Agonists are widely used in poor responders undergoing in vitro fertilization (IVF) to prevent an endogenous luteinizing hormone (LH) surge. Long agonist protocol increases both duration of treatment and total dose of gonadotropins necessary to effect follicular development in poor responders.2 However, agonists due to their initial flare effect may help in recruitment of the follicles. 2 Hence, short agonist protocol where agonist administration is initiated in the early follicular phase before gonadotropin administration is one of the most widely used agonist protocols in poor responders. 2 Microdose flare and ultrashort protocols are preferred by some clinicians, in an effort to minimize the pituitary suppression, but have not shown to improve the clinical outcomes.2 References Data on file (1). Last accessed on 18 January 2021. Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–69.
  5. The antagonist protocols, according to Indian Society for Assisted Reproduction (ISAR ), has been shown on the screen.1 Antagonists provide an effective way of preventing premature luteinizing hormone (LH) surge without prolonging the treatment duration. Pregnancy rates achieved are similar to short agonist protocol.2 References Data on file (1). Last accessed on 18 January 2021. Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–69.
  6. Natural cycle in vitro fertilization (IVF) is used as an alternative to the high-dose regimens in poor ovarian response (POR) to reduce the gonadotropin burden, with possible improvement in oocyte quality, and to reduce the financial burden of high-dose regimens. Modified natural cycle IVF with the addition of antagonists and small doses of follicle-stimulating hormone (FSH) or minimal stimulation combining oral letrozole or clomiphene citrate along with small doses of gonadotropins to improve the number of follicles and successful oocyte retrieval are alternatives to high-dose protocols in women with POR and are widely used when high-dose FSH protocols are unsuccessful.1 However, it is associated with a high risk of cancellation due to abnormal follicular maturation, premature ovulation of the single follicle, failed oocyte retrieval, or empty follicle at retrieval, and failed fertilization.2 References Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–69. Data on file (1). Last accessed on 18 January 2021.
  7. By using novel Patient-Oriented Strategies Encompassing Individualize D Oocyte Number (POSEIDON) criteria, the clinician can, first of all, identify and classify women who are likely to have reduced success in assisted reproductive treatment (ART) or women with low prognosis in ART, and secondly, develop a treatment plan to achieve the individualized oocyte number related to the optimal probability of generating at least one euploid blastocyst for transfer in each POSEIDON's patient category. The POSEIDON group proposed this new classification of ART in patients with diminished ovarian reserve (DOR) or unexpected inappropriate ovarian response and four subgroups have been proposed based on quantitative as well as qualitative parameters which include: age and expected anomaly rate; ovarian biomarkers, such as antral follicle count (AFC) and anti-Mullerian hormone (AMH); and ovarian response – if an earlier stimulation was performed. In practical terms, the POSEIDON criteria stratify the low prognosis patients in two main categories based on oocyte yield, namely, the ‘expected’ low ovarian response (Group 3 and 4) and the ‘unexpected’ low ovarian response (Groups 1 and 2).1,2 POSEIDON’s groups 1 and 2 encompass women who had poor (<4) or suboptimal (4–9) number of oocytes retrieved after a conventional ovarian stimulation (OS) despite the presence of an adequate ovarian reserve, defined by an AFC of 5 and/or an AMH 1.2 nanogram per milliliter (ng/mL). POSEIDON’s groups 3 and 4 encompass women who had poor ovarian reserve, defined by an AFC of <5 and/or an AMH <1.2 ng/mL.1,2 It is anticipated that this new concept of low prognosis will help improve the management of patients undergoing ART, promote a tailored approach to patient handling, and identify more homogeneous populations for clinical trials, thereby, providing better tools with which to maximize in vitro fertilization (IVF) success rates.1 References Esteves SC, Roque M, Bedoschi GM, Conforti A, Humaidan P, Alviggi C. Defining Low Prognosis Patients Undergoing Assisted Reproductive Technology: POSEIDON Criteria-The Why. Front Endocrinol (Lausanne). 2018;9:461. Conforti A, Esteves SC, Cimadomo D, et al. Management of Women With an Unexpected Low Ovarian Response to Gonadotropin. Front Endocrinol (Lausanne). 2019;10:387.
  8. The treatment approach based on Patient-Oriented Strategies Encompassing Individualize D Oocyte Number (POSEIDON) criteria for POSEIDON groups 1 and 2 has been clearly shown on the screen. Reference Conforti A, Esteves SC, Cimadomo D, et al. Management of Women With an Unexpected Low Ovarian Response to Gonadotropin. Front Endocrinol (Lausanne). 2019;10:387.
  9. Progesterone for luteal phase support can be administered orally, intramuscularly, or vaginally with each route having different bioavailability and tolerability profiles. Oral micronized progesterone has low bioavailability and is associated with systemic adverse events such as drowsiness, dizziness, and headache. 1 Intramuscular progesterone is associated with injection-site pain and abscesses. 1 Micronized vaginal progesterone is associated with administration-related side effects such as vaginal irritation. 1 Oral dydrogesterone is a potent oral progestin with improved bioavailability. 1,2 Reference Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: A randomized clinical trial. Hum Reprod. 2018;33(12):2212–2221. Griesinger G, Tournaye H, Macklon N, et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019;38(2):249–259.
  10. Several factors suggest that oral dydrogesterone is the better and convenient option for luteal phase support in assisted reproductive treatment. These include: Approved in threatened and recurrent miscarriage and other progesterone deficiencies1 Greater bioavailability2 Effective at lower dose and causes endometrial transformation2 Minimizes the activation of receptors other than progesterone receptor, and thus minimizes unwanted effects2 Shifts cytokine balance from T-helper (Th)1 toward Th2 cytokine production that is conducive to the success of pregnancy3 Induces nitric oxide synthesis that improves endometrial receptivity and pregnancy outcomes.3,4 Increases progesterone-induced blocking factor production, thereby improving pregnancy success rates.5 Suppression of T-cell and killer-cell activity6 References Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf. Last accessed on 25 January 2021. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003;46 Suppl 1:S7–S16. Raghupathy R, Al-Azemi M. Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone. Am J Reprod Immunol. 2015;74(5):419–426. Abdel-Razik M, El-Berry S, Mostafa A. The Effects of Nitric Oxide Donors on Uterine Artery and Sub-endometrial Blood Flow in Patients with Unexplained Recurrent Abortion. J Reprod Infertil. 2014;15(3):142–146. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol. 2005;53(4):166–171. Faust Z, Laskarin G, Rukavina D. Progesterone‐Induced Blocking Factor Inhibits Degranulation of Natural Killer Cells. Am J Reprod Immunol. 1999;42(2):71–75.
  11. Endometrin = Lutigest 1. Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017;32(5):1019-1027. doi:10.1093/humrep/dex023. 2. Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018;33(12):2212-2221. doi:10.1093/humrep/dey306. 3. Vaisbuch E, Leong M, Shoham Z. Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey. Reprod Biomed Online. 2012;25(2):139-145. doi:10.1016/j.rbmo.2012.04.005. 4. Chakravarty BN, Shirazee HH, Dam P, Goswami SK, Chatterjee R, Ghosh S. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol. 2005;97(5):416-420. doi:10.1016/j.jsbmb.2005.08.012. 5. Crinone 4% and 8% progesterone gel US Physician Information, June 2017. 6. Crinone 8% progesterone gel Australian Product Information, 2 March 2011. 7. Utrogestan 200mg Australian Product Information, 12 July 2016. 8. Utrogestan vaginal 200 mg capsules. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory Agency), October 2015. 9. Kleinstein J. Efficacy and tolerability of vaginal progesterone capsules (UtrogestTM 200) compared with progesterone gel CrinoneTM 8% for luteal phase support during assisted reproduction. Fertil Steril. 2005;83(6):1641–1649. 10. Progesterone 400 mg pessaries. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory Agency), March 2017. 11. Doody KJ, Schnell VL, Foulk RA, et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009;91(4):1012-1017. 12. Endometrin Australian Product Information, 19 September 2012. 13. Lockwood G, Griesinger G, Cometti B, et al. Subcutaneous progesterone versus vaginal progesterone gel for luteal phase support in in vitro fertilization: a noninferiority randomized controlled study. Fertil Steril. 2014;101(1):112-119. 14. Baker VL, Jones CA, Doody K, et al. A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization. Hum Reprod. 2014;29(10):2212-2220. 15. Lubion 25 mg powder for solution for injection. Lubion 25 mg solution for injection. UK Public Assessment Report MHRA (Medicines and Healthcare Products Regulatory Agency)
  12. 1. Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017;32(5):1019-1027. doi:10.1093/humrep/dex023. 2. Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018;33(12):2212-2221. doi:10.1093/humrep/dey306.
  13. Let us summarize the key findings of Griesinger et al. one-step meta-analysis of individual population data. Oral dydrogesterone was associated with Significantly higher pregnancy rate than micronized vaginal progesterone (MVP). Significantly higher live birth rate than MVP Well-established safety profile with no significant maternal or fetal safety concerns. Reference Griesinger G, Blockeel C, Kahler E, et al. Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis. PLoS One. 2020;15(11):e0241044.