1. Prof.Duru Shah Founder President “The PCOS Society” (India)
President Elect of the Indian Society
for Assisted Reproduction (ISAR)
Honorary Fellow of the Royal College
of Obs. & Gyn.
First Indian to receive FIGO’s
“Distinguished Merit Award” for
Services towards women’s health.
Director Gynaecworld….. The Center
for Womens Health & Fertility
Prof.Duru
Shah
Prof.and : Breach Candy Hosp.
Cons. Obs. Jaslok Hospital
& Gyn Global Hospital

2. Poor Responders in PCOS
Prof. Duru Shah
MD FRCOG FCPS FICS FICOG FICMCH DGO DFP
SMART OBGYN
16th April, 2016
Mumbai
Org.by MOGS in asso. with SAFOG,FOGSI & AICRCOG

3. Definition Failure to respond adequately to standard
protocols and to recruit adequate follicles is called
“poor ovarian response”.
This results in decreased oocyte production,
cycle cancellation and, overall it is associated
with a significantly diminished probability of
pregnancy.
Ref: Shanbhag S. et.al. Cochrane Database Syst Rev. 2007;(1):
CD004379

4. Responses to Gonadotropins
3 main groups
Normal Responders
When stimulated aggressively with Gn will develop 5-8 mature follicles as well as several smaller ones.
Poor Responders (older age, poor ovarian reserve)
Failure to produce an adequate no. of mature follicles(<4) & or a peak E2 levels < 500 pg/ml.
High Responders (PCOS)
Defined as those women with peak E2 levels
> 4000 pg/ml on the day of hCG administration or > 15 retrieved oocytes

5. Poor Responders Concept of Poor Ovarian Response introduced 30 yrs.
ago.
Results in ↑ cancellation rates
↓ nos. of oocytes retrieved
↓ preg. rates
Universal definition of Poor
Responders in 2011-
Bologna Criteria – ESHRE
WORKING group.
Re. ASRM Fertil Steril, 2011, 96:

6. Bologna Criteria- 2011
At least two of the following three features must
be present:
Advanced maternal age (≥ 40 yrs.) or any
other risk factor for POR.
A previous POR (≤ 3 oocytes with a
conventional stimulation protocol):
An abnormal ovarian reserve test (ie. AFC
<5-7 follicles or AMH < ng/ml)
Ref. A.P. Ferraretti et. al. Human Reproduction Vol.26, No.7, pp.1616-
1624,2011

7. Risk factors for Poor Ovarian Reserve
Age > 37 yrs., varies with
ethnicity.
Ovarian surgery
Endometriosis
Genetic Defects
Chemo / Radiotherapy
Autoimmune Disorders
Contd…
Ref. A.P Ferraretti et.al. Human Reproduction vol. 26, no. 7 pp
,2011

8. Declining follicle/oocyte numbers with advancing age.
Ref : Gleicher et.al. Reproductive Biology & Endocrinology (2015)
13:34

9. Genetic Defects Under hormonal control
Genetic control which may either slow or
hasten the process of recruitment
Genes identified currently are :
- AMH type II – Receptor gene (AMHR2)
- FMRI Gene ( Fragile X Mental Retardation Gene)
- BRCA1 Gene
Above Genes when mutated, blocked or knocked
out, lead to rapid depletion of primordial follicles.

10. Ovarian Surgery Extensive Ovarian Drilling for PCOS
Contd…
Ovarian Surgery
Extensive Ovarian Drilling for PCOS
Prophylactic oophorectomy→ POF
Salpingectomy for ectopic pregnancy → ↓
AFC→↓ oocytes obtained during ART and for
hydrosalpinx.
Ovarian Cystectomy for endometriomas.
Ovarian Neoplasms in Adolescents
Contd…

11. Other Factors Single Ovary Chronic Smoking New Factors proposed
Contd…
Other Factors
Single Ovary
Chronic Smoking
New Factors proposed
Diabetes Mellitus Type I
N. Soto, G et.al. Human Rep. Vol. 24, no. 11 pp , 2009
Transfusion dependant β Thalassemia
H.H. Chang, M-J et.al. British Journal of Obs. & Gyn. vol. 118,no7, pp
Uterine Artery Embolization
W.J.J. Hehenkamp, et. al. Human Reproduction vol. 22, no.7, pp

12. Identifying Poor Responders
High Risk Group
Day FSH > 10 m IU /ml
- Inhibin B < 45 pg/ml
- AMH < 3 ng/mL
- Total Antral Follicle Count < 10
Age > 37 years of age
- younger pts. may also have a poor
response.

13. Ultrasound –Antral Follicle count
Parameter
Normal responders (n=81)
Poor Responders (n=29) P
Endpoints
Total no. of follicles
17.7±9.7
4.6±2.6
<.001
Total no. of oocytes
14.9±8.1
3.0±1.6
Ongoing pregnancy n(%)
22(24)
2(10)
HOW DOES IT DEVELOP?
Endometriosis remains an enigma despite having been extensively studied. Its aetiology remains unclear, although there is a positive correlation with retrograde menstruation, probably with a background genetic predisposition.
Additional factors that may be important in pathogenesis OF ENDOMETRIOSIS include
- Immunologic abnormalities,
- Endometrial disorders, and
- Peritoneal dysfunction
The cause of endometriosis is not clear, although the predominant theory is that retrograde menstruation is the cause.
Additional factors in pathogenesis include immunologic abnormalities, endometrial disorders, and peritoneal dysfunction, hematologic spread, lymphatic spread, genetic factors and combination of the above.
Ref : Kwee J et al Reprod Biology & Endocrinology :9

14. Hormonal investigations
Parameter
Normal responders (n=81)
Poor Responders (n=29) P
Value
Age at baseline (y)
CD3
.029
FSH(IU/L)
<.001
E2(pmol/L)
138.4±156.5
124.1±54.1
.632
Inhibin B (ng/L)
93.1±43.0
76.0±47.4
.077
AMH(g/L)
3.53±2.46
1.48±2.59
HOW DOES IT DEVELOP?
Endometriosis remains an enigma despite having been extensively studied. Its aetiology remains unclear, although there is a positive correlation with retrograde menstruation, probably with a background genetic predisposition.
Additional factors that may be important in pathogenesis OF ENDOMETRIOSIS include
- Immunologic abnormalities,
- Endometrial disorders, and
- Peritoneal dysfunction
The cause of endometriosis is not clear, although the predominant theory is that retrograde menstruation is the cause.
Additional factors in pathogenesis include immunologic abnormalities, endometrial disorders, and peritoneal dysfunction, hematologic spread, lymphatic spread, genetic factors and combination of the above.
Contd..
Ref : Kwee J et al Reprod Biology & Endocrinology :9

15. Value of AMH as a prognostic indicator of IVF outcome
Study
To evaluate AMH values to predict oocyte yield,
cycle cancellation and pregnancy outcomes.
Retrospective study of IVF patients in an
academic center.
2760 pts. – 4072 cycles of IVF with both Agonist
and Antagonist cycles.
Contd….
Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April
2014

16. AMH levels at various ages
Patient Age in years.
< 35
35-37
38-40
41-42
>42
Total
<0.17 7 24 40 21 42
134 27 74 59 60
260
101
139
189
152 95
676 94 87
115 56 37
389
213
147
165 89 33
647
181 91 90 31
414
>4.00
133 65 29 9 4
240
756
593
702
417
292
2760
Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4
April 2014

17. Oocytes retrieved according to age & AMH
Patient Age
Mean oocytes
<0.17
<35
4.8
35-37
4.9
38-40
4.1
41-42
4.2
>42
3.6
13.4
11.5
11.9
11.2
12.1
AMH
Patient Age
Mean oocytes
<35
15.3
35-37
14.3
38-40
13.5
41-42
12.8
>42
15.6
>4.00
15.1
15.9
14.5
15.8
12.7
Contd….
Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4
April 2014

18. Clinical Pregnancy correlated with AMH & age
(ng/mL)
<35
yrs.
35-37
38-40
41-42
>42
>4.00
60.5(114)
63.0(54)
57.7(26)
80.0(5)
0(2)
56.2(169)
48.2(81)
59.2(76)
30.0(30)
15.8(19)
51.6(184)
52.9(136)
42.5(146)
35.8(81)
28.6(28)
46.8(79)
51.3(76)
39.8(103)
36.7(49)
3.0(33)
42.7(82)
42.0(112)
41.2(153)
29.2(113)
5.6(71)
26.3(19)
32.1(28)
34.0(50)
22.5(40)
8.6(35)
<0.17
40.0(5)
33.3(12)
24.0(25)
25.0(12)
3.9(26)
Adj-P for trenda
.002
.016
.003
.268
.095
Ref. David Reichman et.al. Fertil Steril Vol. 101, No.4 April 2014

19. Folliculogenesis
Ref. A La. Marca et.al. Human Reproduction Update, Vol.16, 2010
No.2 pp

20. Folliculogenesis AMH corelates well with AFC, IVF out come.
AMH expression starts after growth initiation
of primordial follicles and disappears after the
small Antral follicles stage in the ovaries.
Ref. Fanchin R. et. al. Hum. Reprod. 18,

21. Folliculogenesis in PCOS
AMH significantly ↑ in PCOS reflecting ↑
Primordial count.
Median density of primary follicles seen in
ovarian biopsies is 6 times ↑ in anovulatory
PCO v/s normal ovaries, suggesting
a larger ovarian reserve.
Ref. Laven J. et.al. (2004) J. Clin Endocrinol Metab 89,

22. Folliculogenesis in PCOS
Women with PCO are born
with a larger pool of resting foll.
- genetically determined process
which occurs in fetal life.
Larger the pool of Primordial
follicles → ↑ chance of PCOS in a certain environment.
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10 pp ,2004

23. Folliculogenesis in PCOS
Women with PCO are unlikely to undergo a rapid depletion of their ovarian reserve too early.
Hence Poor responders to ovarian stimulation in PCO women are rarely seen.
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10 pp ,2004

24. Ovarian Aging Normal Ovarian Ageing
→ ↓ oocyte quality and quantity rapidly in late
thirties.
Early Ovarian Ageing seen in 10% of women
→ ↓ oocyte quantity which is faster than
qualitative decline before age 32 yrs.
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp ,
2004

25. Early Ovarian Aging- are women with PCOS protected?
AFC- good predictor of ovarian response and
corelates well with chronological age.
PCO women have a higher no. of AFC
PCO ovaries tend to be larger and have ↑ peak
stromal blood flow velocity on Doppler studies.
PCOS women have ↑ Day 2 Inhibin B levels and
↑ early follicular VEGF levels.
Contd..
Ref. Nikolaou & Templeton A (2003) Hum Repro. 18,
Nikolaou D & Templeton A (2004) Eur J. Obstet Gynaecol 113,

26. Early Ovarian Aging- are women with PCOS protected?
Contd..
Early Ovarian Aging- are women with PCOS protected?
Using AMH + AFC
Women with PCOS perform better with ovarian
reserve tests as compared to women with normal
ovaries.
Poor response to ovarian stimulation is a
predictor of early ovarian ageing v/s larger
number of oocytes recruited during ovarian
stimulation, increasing the risk for developing
OHSS
Contd..
Ref. Nikolaou & Templeton A (2003) Hum Repro. 18,
Nikolaou D & Templeton A (2004) Eur J. Obstet Gynaecol 113,

27. Early Ovarian Aging- are women with PCOS protected?
PCO (older data)
→ Large no. of follicles with compromised
quality due to ↓ fertilization rates
↑ miscarriage rates
↑ recurrent miscarriage rates
PCO (recent data)
Above true only if PCOS exists ie. Polycystic
ovaries (PCO) associated with
→ menstrual irreg.
→ Hyperandrogenism (PCOS)
→ Associated Insulin Resistance (IR)
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp , 2004

28. Early Ovarian Aging- are women with PCOS protected?
More oocytes
More embryos
↑ cumulative preg. rates
Similar miscarriages rates as
normal women.
Comparable oocyte quality
Time to pregnancy similar
Hence women with PCOS, but no clinical PCOS,
have a larger no. of good quality oocytes
Ref. Rai et.al Hum. Reprod. 15,

29. Clinical Pregnancy correlated with AMH & age – Our data
ART : 369 pts.
Age
No. of pts.
Mean AMH
Oocytes
Retrieved at OPU
Preg. rate
26- 30 93
3.86 13
41.93%
31-35
151
2.98 10
34.43%
36 – 40 78
1.59 6
25.64%
>40 47
0.5 3
10.64%
Ref. Gynaecworld data

30. Pregnancy rates correlated with Age + AMH (PCOS pts)
Total no. of pts
Patients age in years
No. of Pts.
AMH
Ng/ml
<30
(n=26)
31-35
(n=88)
>36
(n=66) 29 ≤1
16.70%
18.20%
14.60% 64
1.1 –3
33.10%
32.40%
22.30% 47
3.1- 6
38.46%
34.50%
23.30% 49
≥ 6.1
39.90%
35.40%
24.60%
Ref. Gynaecworld data

31. Pregnancy rates correlated with Age + AMH (Non PCOS pts)
Total no. of pts
Patients age in years
No. of Pts.
AMH
Ng/ml
<30
(n=26)
31-35
(n=88)
>36
(n=66) 41 ≤1
20.00%
15.00%
10.50% 83
1.1 – 3
33.30%
40.00%
21.10% 36
3.1- 6
35.70%
34.20%
22.20% 20
≥ 6.1
36.80%
35.60%
22.80%
Ref. Gynaecworld data

32. Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve
Study
91 pts. with confirmed PCOS and 87 healthy controls included in the study.
Diagnosed bet 1987 and 1995, at the time of the follow-up subjects were 35 yrs. of age or older.
Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

33. Contd..
Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve
Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

34. Long-term follow-up of patients with PCOS syndrome: reproductive outcome and ovarian reserve
Premenopausal women without hormone treatment
PCOS (n=52)
Controls (n=56)
Age (yrs.)
42.4 ± 4.5
41.5 ± 4.6
Ovarian volume (ml)
9.5 ± 0.9**
6.6 ± 0.5
Antral follicles (n)
11.7 ± 1.7***
5.0 ± 0.3
Estradiol (pmol/1)
514 ± 79 *
710 ± 90
Testosterone (nmol/1)
1.5 ± 0.1**
1.0 ± 0.1
SHBG (nmol/1)
50.4 ± 4.5*
64.0 ± 4.8
FAI
5.1 ± 0.8**
2.0 ± 0.2
FSH (U/I)
6.2 ± 1.1*
9.6 ± 1.3
LH(IU/I)
7.1 ± 0.7
10.4 ± 1.7
AMH(pmol/I
39.9 ± 6.1***
15.7 ± 2.1
* p<0.025
** p<0.01
***p<0.001
Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

35. Ovarian Volume Contd.. Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

36. Antral Follicles Contd.. Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

37. AMH
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

38. Reproductive outcome did not differ between
Contd..
Results:
Reproductive outcome did not differ between
women with a previous diagnosis of PCOS and
healthy control subjects.
Ovarian reserve better preserved in women
with PCOS
Live birth rate and rate of miscarriages similar in
PCOS patients and control women.
Contd..
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

39. Mean ovarian volume and number of antral
Contd..
Results:
Mean ovarian volume and number of antral
follicles, significantly higher in PCOS patients.
PCOS patients have markedly higher serum
concentration of AMH.
More than two-thirds of the PCOS patients in the
present study reported at least one
spontaneous pregnancy.
PCOS patients have a good fecundity.
Ref. M. Hudecova et.al. Hum. Repro. Vol.24, No 5 pp ,2009

40. FMRI Gene her-norm / low sub- genotype
PCO like ovarian phenotype at young ages
large number of eggs recruited in the
maturation process.
Leading to DOR in older age
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp ,
2004

41. FMRI Gene her-norm / high FMRI genotype
Slow recruitment of immature eggs at young
ages.
Good ovarian reserve at advanced ages
(above 42 years)
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp ,
2004

42. Conclusions
Recent findings support that, women with PCOS are born with a larger pool of resting follicles, almost certainly genetically determined.
The rate of decline of the ovarian reserve
depends on the number of remaining
primordial and small pre-antral follicles.
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp ,
2004

43. Conclusions Hence women with PCO are unlikely to
undergo a rapid depletion of their ovarian
reserve too early.
PCO most likely forms a low-risk group for
early ovarian aging and poor ovarian
response
Contd..
Ref. D. Nilolaou et.al. Hum. Reprod. Vol. 19, No.10, pp ,
2004