Management of ART cycle of women with poor ovarian response.

1. Poor Ovarian Responders
ART Options
Tevfik Yoldemir MD, BSc, MA, PhD
Marmara University, School of Medicine, Istanbul, Turkiye
tevfik.yoldemir@marmara.edu.tr
Photo
(compulsory)

2. I have no financial relationships to disclose.

3. The ESHRE consensus Bologna Criteria
• At least two of the following three criteria must be met to be
considered as a poor responder to COS:
(1) age 40 years or any other risk factor for poor response,
(2) a previous poor response (3 oocytes in a conventional COS cycle),
(3) an abnormal ovarian reserve test (defined as AFC < 5–7 or serum
AMH level <0.5–1.0 ng/mL)
OR
Two episodes of POR after maximal stimulation
Hum Reprod. 2011;26:1616–1624

4. POSEIDON classification
(Patient-Oriented Strategies Encompassing Individualized Oocyte Number)
Fertil Steril. 2016;105:1452–1453.
Reprod Biol Endocrinol 2018;16:20
JBRA Assist Reprod. 2021 Apr 27;25(2):282-292

5. Antral follicle count and anti-Mullerian hormone to
classify low-prognosis women
prediction of low oocyte yield
( <4 retrieved oocytes)
prediction of suboptimal oocyte
yield ( 4–9 retrieved oocytes).
Hum Reprod. 2021 May 17;36(6):1530-1541.

6. Long GnRH agonist protocol or a GnRH
antagonist protocol
Daily subcutaneous injections of
recombinant FSH monotherapy,
recombinant FSH combined with
recombinant LH (2:1 ratio), or
recombinant FSH combined with either
recombinant LH or highly purified hMG
Initial daily gonadotropin doses varied
between 150 IU and 450 IU.
Final oocyte maturation was triggered by
subcutaneous administration of either
recombinant hCG (250 mcg) or 0.2 mg
GnRH agonist (0.2 mg triptorelin)
The estimated prevalence of POSEIDON patients in the
general population undergoing IVF/ICSI.
Front Endocrinol (Lausanne). 2021 Mar 12;12:630550.
∼80%

7. Cumulative live birth rates in patients with poor
ovarian response
Fertil Steril 2018;109:1051–9
3391 women
5243 IVF cycles

8. The conservative cumulative live birth rates
stratified according to age
Fertil Steril 2018;109:1051–9
The conservative cumulative live birth rate assumes that patients who did
not return for treatment did not have a pregnancy resulting in a live birth.
poor ovarian response
(according to the Bologna
criteria)
3391 women
5243 IVF cycles

9. The optimistic cumulative live birth rates stratified
according to age
Fertil Steril 2018;109:1051–9
The optimistic cumulative live birth rate is based on the assumption that
patients who did not return for treatment had the same chance of a pregnancy
resulting in a live birth as those who remained in treatment
poor ovarian response
(according to the Bologna
criteria)
3391 women
5243 IVF cycles

10. Cumulative live birth rates for low-prognosis women
Chen et al. BMC Pregnancy and Childbirth (2022) 22:233
POSEIDON group 1 (younger unexpected poor responders, n=4470),
POSEIDON group 2 (older unexpected poor responders, n=2270),
POSEIDON group 3 (younger expected poor responders, n=1110),
POSEIDON group 4 (older expected poor responders, n=1095), and
group 5 (Control group, n=8753).
Progestin-primed ovarian stimulation (PPOS) approach
Oral medroxyprogesterone acetate (MPA, 4-10 mg/d),
Utrogestan (200 mg/d,), Duphaston (DYG, 20 mg/d)
Single use of hCG (5000–10,000 IU) or a dual trigger
consisting of a low dose of hCG (1000 IU) and
Decapeptyl 0.1 mg
Natural cycles were employed for patients with a regular
menstrual cycle.
Hormone therapy or stimulation cycles were employed for
patients with irregular menstrual cycles

11. Chen et al. BMC Pregnancy and Childbirth (2022) 22:233
Cumulative live birth curves for low-prognosis women over
5 years.
The conservative competing risk approach
assumed that patients who discontinue ART
treatment would have a live-birth rate of zero.
The optimistic analysis approach assumed that
patients who stop treatment would have the same
chances of pregnancy as those who continue
treatment.
38%
27%
60%
40%

12. Cumulative live birth curves for low-prognosis women over
9 FET cycles.
Chen et al. BMC Pregnancy and Childbirth (2022) 22:233
The optimistic analysis approach assumed that
patients who stop treatment would have the same
chances of pregnancy as those who continue
treatment.
The conservative competing risk approach
assumed that patients who discontinue ART
treatment would have a live-birth rate of zero.
75%
48%
55%
30%

13. The optimal estimated CLBR assumes that
women who discontinued IVF/ICSI treatments
would have live-birth rate similar to those
continuing treatments. AGING 2021, Vol. 13, No. 10, pp 14385-14398
The conservative estimated CLBR assumes that
women who discontinued IVF treatments would have
a live-birth rate of zero if they continued treatments.
An estimate of cumulative live birth rates
over multiple IVF/ICSI cycles
70%
40% 25%
45%

14. The optimal and conservative estimated cumulative live birth rates
stratified by ovarian reserve in different age groups.
AGING 2021, Vol. 13, No. 10, pp 14385-14398
The optimal estimated CLBR assumes
that women who discontinued IVF/ICSI
treatments would have live-birth rate
similar to those continuing treatments.
The conservative estimated CLBR
assumes that women who discontinued
IVF treatments would have a live-birth
rate of zero if they continued treatments.
75% 55%
45% 35%
45%
25%
45%
25%

15. The optimal and conservative estimated cumulative live birth rates
stratified by ovarian reserve in different age groups.
AGING 2021, Vol. 13, No. 10, pp 14385-14398
40%
20%
15%
25%
The optimal estimated CLBR assumes
that women who discontinued IVF/ICSI
treatments would have live-birth rate
similar to those continuing treatments.
The conservative estimated CLBR assumes
that women who discontinued IVF treatments
would have a live-birth rate of zero if they
continued treatments.

16. Cumulative delivery rate per aspiration
IVF/ICSI cycle in POSEIDON patients N=9073
Hum Reprod. 2021 Jul 19;36(8):2157-2169.
GnRH antagonist protocol or the long GnRH agonist protocol
Patients received 150–450IU daily subcutaneous injections of (i)
recombinant FSH (rec-FSH),
(ii) highly purified human menopausal gonadotropin (hMG),
(iii) rec-FSH combined with hMG, or
(iv) recombinant FSH combined with recombinant LH (2:1)
Both fixed and flexible GnRH antagonist protocols were used.
Final oocyte maturation was carried out with either hCG or GnRH
agonist.
FET was performed in a hormone replacement treatment cycle without
GnRH down regulation
26%
12%

17. Cumulative delivery rate per aspiration
IVF/ICSI cycle in POSEIDON patients N=9073
Hum Reprod. 2021 Jul 19;36(8):2157-2169.
14%
12%
30%

18. Mild ovarian stimulation versus conventional IVF in
women considered to be poor responders
• There is fair evidence that clinical pregnancy rates after IVF are not
substantially different when comparing mild ovarian stimulation protocols
using a combination of oral agents and low-dose gonadotropins ( ≤150
IU/d) to conventional-gonadotropin protocols.
• There is insufficient evidence to recommend for or against IVF with mild
ovarian stimulation using oral agents alone over conventional-
gonadotropin stimulation.
• There is fair evidence that clinical pregnancy rates after IVF are not
substantially different when comparing natural-cycle protocols to
conventional-gonadotropin protocols.
• Mild ovarian-stimulation protocol (low-dose gonadotropins with or without
oral agents) have comparable low pregnancy rates similar to that of
conventional gonadotropin protocols.
Fertil Steril. 2018 Jun;109(6):993-999.
Doi:10.1016/j.fertnstert.2018.03.019

19. Mild or Conventional GnRH-Antagonist
Poseidon Group 4 Poor Responders
Front. Reprod. Health 2020; 2:606036
Mild stimulation
(100 mg Clomiphene Citrate from day 2
to day 7, hMG 75 IU per day from day 7)
Conventional stimulation
(FSH 300–375 IU per day + r.LH 75–150
IU per day from day 2)
Follicular Output RaTe (FORT): calculated
as the ratio of pre-ovulatory follicle count
(from 16 to 22 mm in diameter) on day of
triggering / Antral follicle count under
transvaginal ultrasound scans)
Follicle to oocyte index (FOI): the ratio of
the number of retrieved oocyte / antral follicle
count)

20. Clomiphene citrate and gonadotropin dose on ovarian
response markers and IVF outcomes in poor responders
Hum Reprod 2021 Mar 18;36(4):987-997
doi:10.1093/humrep/deaa336
Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG,
Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG,
Group C (n = 30) received placebo and a starting dose of 450 IU HMG and
Group D (n = 27) received placebo and a starting dose of 150 IU HMG.
Ovarian stimulation with 150 IU gonadotrophin in combination with 100
mg CC produced more blastocysts.

21. Letrozole co-treatment
POSEIDON groups 3 and 4
Archives of Gynecology and Obstetrics (2022) 306:1313–1319

22. Modified natural cycle IVF versus conventional
stimulation in advanced-age Bologna poor responders
Reprod Biomed Online. 2019 Oct;39(4):698-703
There was no significant difference between treatment groups.
MNC-IVF, could be a reasonable alternative in this difficult-to-
treat group of women
(hp-HMG) 75 IU & (GnRH) antagonist
0.25 mg/day were started concomitantly
when a follicle with a mean diameter of
14 mm was present on ultrasound scan.
(HCG) 5000 IU was administered as soon
as the mean follicular diameter was
≥16 mm

23. Mild ovarian stim / GnRH Antagonist / Depot GnRH agonist
POSEIDON group 3
the depot GnRH agonist
protocol
Int J Gynaecol Obstet.
2022 Jun;157(3):733-740.
mild ovarian stimulation
protocol
the GnRH antagonist
protocol

24. Human Menopausal Gonadotropin
Live Birth Rates Poseidon Group 3 and 4
Reproductive Sciences (2021) 28:488–494

25. Natural Cycle - Advanced-Age Poor Responders
Advanced maternal age: patients over 40 years old and at least one of the following:
• Abnormal ovarian reserve biomarker: AMH < 0.5– 1.1 ng/mL; AFC < 5–7
• Previous POR: ≤ 3 oocytes with conventional stimulation
• Two episodes of POR after maximal stimulation
Reproductive Sciences (2021) 28:1967–1973
From the 6th day of the cycle, patients underwent
transvaginal sonography to monitor follicle size.
When follicle size reached 16 mm in mean diameter,
triggering ovulation with 10,000 IU of human chorionic
gonadotropin

26. Estrogen priming through luteal phase and stimulation
phase in poor responders
J Assist Reprod Genet. 2012
Mar;29(3):225-30.
DOI 10.1007/s10815-011-9685-7

27. Estrogen priming through luteal phase and stimulation
phase in poor responders
J Assist Reprod Genet. 2012
Mar;29(3):225-30.
DOI 10.1007/s10815-011-9685-7
oral estradiol valerate (E2)
4 mg, was initiated on luteal
day 21 and stopped at day
3 in the next menstrual
cycle(Protocol A)
or
continued during the period
of ovarian stimulation until
the day of hCG injection
(Protocol B)
Compared to standard GnRH antagonist protocol, cancellation rate was lower with
luteal E2 group

28. Luteal estradiol priming in women
defined as poor responders
Human Reproduction, 2013 Vol.28, No.11 pp. 2981–2989

29. Human Reproduction, 2013 Vol.28, No.11 pp. 2981–2989

30. Human Reproduction, 2013 Vol.28, No.11 pp. 2981–2989

31. CoQ10 200 mg x3 / day for 60 days preceding
IVF-ICSI cycle POSEIDON classification group 3
Reproductive Biology and Endocrinology (2018) 16:29

32. Dehydroepiandrostendione sulphate and prediction
of live birth after IVF young women with low AMH
AMH cut-off value for the poor ovarian response
was arbitrarily set at 6.5 pmol/l (0.91 ng/ml)
Reproductive BioMedicine Online 2014; 28: 191– 197
DHEA-S convertion
5.4 mmol/l =1.99 mg/ml
ANTA 300 HMG/ 10000 IU HCG / 1500 IU HCG + PROG 200x3 VAG

33. DHEA or testosterone versus placebo/no treatment,
Live birth/ ongoing pregnancy rate.
Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD009749.

34. Growth Hormone (GH) Improvement of Ovarian Responses
Asian Pac J Cancer Prev. 2019 Jul 1;20(7):2033-2037.
DOI:10.31557/APJCP.2019.20.7.2033
Somatropin,
2.5mg/day,
subcutaneously
from the eighth
day of the cycle
Somatropin,
0.1mg/day,
subcutaneously
from the third
day of the
previous cycle
Normal saline,
0.1mg/day,
subcutaneously)
from the eighth
day of the cycle
N= 32 / 34 / 26

35. GH co-treatment during ovarian
stimulation in poor ovarian responders
• A systematic review and meta-analysis on this topic by Cozzolino et al. cast doubt on a
beneficial effect of GH on live birth rates in poor responders (2020).
• It included 12 RCTs of poor ovarian responders undergoing a single IVF/ICSI cycle with GH
supplementation versus conventional controlled ovarian stimulation, with the primary outcome
of live birth rate, and secondary outcomes of clinical pregnancy rate (CPR), miscarriage rate,
ongoing pregnancy rate (OPR), number of oocytes, number of mature (metaphase II [MII])
oocytes and the number of embryos available for transfer.
• Between the 586 women assigned to the intervention and the 553 assigned to the control
group, there was no significant difference in live birth rate (risk ratio 1.34, 95% CI 0.88-2.05),
miscarriage rate or ongoing pregnancy rate.
• GH supplementation was associated with an increased CPR, number of oocytes retrieved
(mean difference 1.62), number of MII oocytes (mean difference 2.06), and number of embryos
available to transfer (mean difference 0.76).
• The authors concluded that GH supplementation in poor responders may improve some
reproductive outcomes, but not the most crucial outcome of live birth rates
Front. Endocrinol. 13:1055097. December 2022

36. DuoStim strategy in poor ovarian responders
Reproductive Biology and Endocrinology (2020) 18:102
304 women

37. Comparison of outcomes at FPS stage of different
trigger medicine at FPS stage
Reproductive Biology and Endocrinology (2020) 18:102

38. Comparison of outcomes at LPS stage of different
trigger medicine at FPS stage of DuoStim protocol
Reproductive Biology and Endocrinology (2020) 18:102

39. Comparison of outcomes at LPS stage of different
trigger medicine at LPS stage of DuoStim protocol
Reproductive Biology and Endocrinology (2020) 18:102

40. Ther Adv Reprod Health 2021, Vol. 15: 1–13

41. Ther Adv Reprod Health 2021, Vol. 15: 1–13

42. Ther Adv Reprod Health 2021, Vol. 15: 1–13

43. Tailored mode and timing of final follicular maturation
Journal of Ovarian Research (2015) 8:69
DOI 10.1186/s13048-015-0198-3

44. Triggering final follicular maturation- hCG,
GnRH-agonist or both, when and to whom?
Journal of Ovarian Research (2015) 8:60
DOI 10.1186/s13048-015-0187-6
GnRHa is now offered concomitant to the standard
hCG trigger dose, to improve oocyte/embryo yield and
quality.
GnRHa and hCG may be offered concomitantly, 34–37
h prior to oocyte retrieval (dual trigger)
or
40 h and 34 h prior to oocyte retrieval, respectively
(double trigger) in patients with abnormal final
follicular maturation.

45. Optimal embryo transfer strategy in poor response
In group 1, 879 poor response cycles
were extracted, 645 from period 1 (group
A, cleavage stage), and 234 from period
2 (group B, blastocyst stage).
In group 2,1384 normal response cycles
were extracted, 676 from period 1 (group
C, cleavage stage), and 708 from period
2 (blastocyst stage).
In subgroup analyses, group A was
divided into subgroup A1 (day 2) and
subgroup A2 (day 3), group B was
divided into subgroup B1 (fresh day 5
ET) and subgroup B2 (frozen-thawed
day 5 FET), group C was divided into
subgroup C1 (day 2) and subgroup C2
(day 3), and group D was divided into
subgroup D1 (fresh day 5 ET) and
subgroup D2 (frozen-thawed day 5 FET)
J Assist Reprod Genet
(2017) 34:79–87
group B,
blastocyst stage
group A,
cleavage stage
B1 fresh day 5 ET
B2 frozen-thawed day 5 FET

46. Optimal embryo transfer strategy in poor response
In group 1, 879 poor response cycles
were extracted, 645 from period 1
(group A, cleavage stage), and 234
from period 2 (group B, blastocyst
stage).
In group 2,1384 normal response
cycles were extracted, 676 from period
1 (group C, cleavage stage), and 708
from period 2 (group D, blastocyst
stage).
In subgroup analyses, group A was
divided into subgroup A1 (day 2) and
subgroup A2 (day 3), group B was
divided into subgroup B1 (fresh day 5
ET) and subgroup B2 (frozen-thawed
day 5 FET), group C was divided into
subgroup C1 (day 2) and subgroup C2
(day 3), and group D was divided into
subgroup D1 (fresh day 5 ET) and
subgroup D2 (frozen-thawed day 5
FET)
J Assist Reprod Genet
(2017) 34:79–87
group C,
cleavage stage
group D,
blastocyst stage
D1 fresh day 5 ET
D2 frozen-thawed day 5 FET

47. POSEIDON classification
Front. Endocrinol. 10:814. 20 November 2019

48. Logistic regression analysis of 1,220 trophectoderm biopsies
from 436 patients undergoing ICSI and PGT-A by NGS.
Front. Endocrinol. 10:814. 20 November 2019

49. The results of single TE biopsy of all biopsied
blastocysts
Human Fertility,2019 23:4, 256-267

50. Predicting the Number of Metaphase II Oocytes Required
for Obtaining at Least One Euploid Blastocyst for Transfer
Front Endocrinol (Lausanne). 2020 Jan 24;10:917.
https://groupposeidon.com/

51. Interventions in patients classified as
POSEIDON 3 and 4 patients
Hum Reprod. 2021 Jul 19;36(8):2157-2169.

52. Interventions in patients classified as
POSEIDON 3 and 4 patients
Hum Reprod. 2021 Jul 19;36(8):2157-2169.

53. SWOT analysis of 4 groups of low prognosis
patients defined by POSEIDON criteria
Front. Endocrinol. 10:409 26 June 2019

54. Poseidon 1 & 2 Poseidon 3 & 4
Front. Endocrinol. 2019 10:614.
doi: 10.3389/fendo.2019.00614
Front. Endocrinol. 2019 10:387.
doi: 10.3389/fendo.2019.00387

55. Poseidon 1& 2
Front. Endocrinol. 2019 10:387.
doi: 10.3389/fendo.2019.00387
Front. Endocrinol. 2019 10:614.
doi: 10.3389/fendo.2019.00614
Poseidon 3 & 4

56. Thank you for you attention.
tevfik.yoldemir@marmara.edu.tr
TevfikYoldemirMDBBAM profdrtevfikyoldemir Tevfik-Yoldemir