This document provides information about Prof. Duru Shah, an expert in polycystic ovary syndrome (PCOS) and infertility. It summarizes her credentials and positions held, and then discusses an overview of PCOS and infertility, including the pathophysiology of PCOS, major challenges in managing infertility for women with PCOS like obesity and hyperinsulinemia, and best practices for ovulation induction. It also reviews predictive markers for ovarian response and results from assisted reproductive technologies for PCOS patients.

1. Duru Shah
Prof.Duru Shah
MD FRCOG
FCPS, FICS
FICOG, FICMCH
DGO DFP
• Founder President of the PCOS Society, India
• President Elect of the Indian Society for
Assisted Reproduction (ISAR).
• Director, Gynaecworld – the Center for
Women’s Health and Fertility.
• Founder- Chairperson
Women’s Empowerment (WE) Foundation
• First & only Indian to receive the
“Distinguished Merit Award” from FIGO
for services toward womens’ health.

2. Duru Shah
Prof. Duru Shah
MD FRCOG FCPS FICS FICOG FICMCH DGO DFP
PCOS & Infertility- Overview
Fertility Forum
15.05.2016
Organized by The PCOS Society, India
Supported by USV

3. Duru Shah
• Polycystic Ovary Syndrome
(PCOS) is one of the most
common endocrinopethies.
• Affects 6% - 7% of
reproductive age women.
Ref: Azziz R. et.al. : J Clin Endocrin . Metab 2004: 39
PCOS

4. Duru Shah
1999 Criteria
(both 1+2)
• Chronic Anovulation
• Clinical and / or
biochemical signs of
hyperandrogenism
and exclusion of
other etiologies.
2003 Rotterdam Criteria
(2 out of 3)
• Oligo and / or anovulation
Clinical and / or biochemical
signs of hyperandrogenism.
• Polycystic ovaries and
exclusion of other etiologies
PCOS – Definition
Revised 2003 Consensus on diagnostic criteria

5. Duru Shah
PCOS - Infertility
Areas for Discussion
• Pathophysiology
• Challenges in infertility management in PCOS
- Obesity
- Hyperinsulinaemia & Hyperandrogenaemia
- ↑ LH
• Ovulation Induction - Best practices
• Useful markers for management
• Conclusions

6. Pathophysiology
• Etiology of PCOS unknown.
Increasing evidence to support the view
Complex Endocrine Trait
Contribution of several genes
(CYP 17, CYP 11a VNTR etc)
Act jointly with Environmental + Nutritional factors
PCOS
Abnormal Ovarian Steroidogenesis
Contd..

7. • Hypersecretion of LH
40% of pts. ↑ LH →menstrual disorders infertility
→ ↑ ovarian androgen production
→ direct interference with oocyte
maturation
↓ ovulation rates &
↑ abortion rates
→ ↓ implantation & pregnancy
rates in ART cycles
Pathophysiology

8. Hyperinsulinemia
Liver
Hyperandrogenaemia
Obesity Insulin
resistance
Polycystic
Ovarian
Syndrome
Pathophysiology of PCOS
↓ sex hormone
Binding globulin
↑ Insulin –like growth
Factor 1
↓ Insulin-like
Growth factor 1
Binding protein
↑ Luteinizing
hormone
Ovary Thecal
Cell hyperplasia
Anovulation
Courtesy : www blackwell-synergy.com
Obesity

9. Ovulation
Fertilization
Implantation
Fetal Viability
Healthy Live born
Poor Oocyte
Quality
Affects gestational
diabetes and
hypertension
Endometrial
receptivity
Hyperinsulinemia
Why does PCOS lead to infertility?

10. PCOS- Major Challenges in infertility
management
• Hyperandrogenaemia
• Hyperinsulinemia
• Obesity
• Premature LH Surge

11. Strategies to optimize fertility in
PCOS women
• Weight loss
• Insulin Sensitizers
• Ovulation Induction
• Laparoscopic Ovarian
drilling
• Assisted Reproduction
Contd…..

12. Obesity
&
PCOS

13. Obesity & Infertility
Facts:
• Obese women 3 times more likely to have infertility v/s
normal women.
• 80% PCOS have ↑ BMI
• Infertility rate ↑ x 4 times / BMI unit
• Central obesity ↓ conception by 30% per cycle for each
0.1 ↑ in W.H. Ratio
• RR of anovulation v/s normal wt. women
- 1.3 times with BMI 24-31 kg/ m2
- 2.7 times with BMI > 31 kg/ m2
Ref. Lisa J. Moran, et.al. Endocrinol Metab Clin N Am 40 (2011) 895-906

14. Obesity & Infertility
• Follicular fluid insulin and androgen levels corelate
with BMI in obese infertile women even in absence of
PCOS. ↑ BMI →
Ref. Franks S, et.al. Hum Reprod Update 2008;14:367-78
Contd…
↑ androgens
Premature follicular atresia
↓ follicular maturation
anovulation Infertility

15. Obesity & Infertility
Obesity
↑ Adipokines (leptin, TNF- ά, IL – 6)
→ antagonise effect of Insulin
→ Insulin Resistance
→ Negative effects on oocyte development, embryo
development, endometrial receptivity.
Ref. Lisa J. Moran, et.al. Endocrinol Metab Clin N Am 40 (2011) 895-906
Contd…

16. Obesity PCOS & Infertility
3586 obese women, 25% with PCOS
Ref. Wang JX et. al. BMJ 2000;321:1320-1
0
10
20
30
40
50
60
70
80
90
100
↓ 50% 95% CI 0.32,0.77)
27% (95 % CI 0.57, 0.96) P <.001
BMI / Kg/m2
Normal < 25 25 - 29 30 - 34 >35

17. • 5 % - 10% wt. loss can improve I.R, ovulation rate,
pregnancy rate even if BMI > normal range
• No consensus on commencement of fertility Rx
based on optimal BMI.
Ref. Practice Committee of ASRM – Obesity & Reproduction Fertil Steril
2008, 90:S21-9 Contd…
Weight loss in infertile obese PCOS
Ref. Clark AM, et. al. Hum Reprod 1998;13:1502-5
ASRM recommends that though BMI of < 35 should be
achieved before conception, “the benefits of postponing
pregnancy to achieve wt. loss must be balanced against
risk of declining fertility with advancing age.

18. Obesity in PCOS- Treatment
• Diet
• Exercise
• Bariatric surgery may be considered for obese
PCOS pts.
• Pharmacological Rx
• Bariatric Surgery
Not recommended for
Ovulation Induction
Wt. loss is the first line therapy in obese
women with PCOS
Ref. Palomba et.al. Hum. Reprod. 2010 , Nov. 25 :11

19. Obesity in PCOS
Ref. Palomba et.al. Hum. Reprod. 2010 , Nov. 25 :11
96 overweight and obese CC Resistant PCOS pts.
SET + Hypo-
calorie diet
2 wks. obser.
Followed by one
cycle of CC therapy
SET plus hypocalorie
diet for 6 wks. + 1 cycle
of CC after 2 weeks
Ovulation rate 12.5 % +
P= .05
RR = 3.9
9.4 %
Ovulation rate 37.5% +
P= .008
RR= 4
SET= Structural Exercise Training
A B C
Significant improvement in
clinical & biochem. androgen &
insulin sensitivity index.

20. Hyperinsulinaemia
&
Hyperandrogenemia

21. Hyperinsulinemia
• Insulin Resistance (IR) is
present in approx. 50% of
women with PCOS.
• 90% of obese women with
PCOS have IR
• IR exacerbates ovulation
dysfunction.
Ref. William Hurd et.al. Fertil Steril, Vol96, Oct 2011

22. Hyperinsulinaemia & PCOS
10
9
8
7
6
5
4
3
2
1
0
0 30 60 90 120 0 30 60 90 120
150
100
50
0
Glucose Tolerance Curves
( mmols / L )
Glucose Stimulated Insulin
Concs. ( mu / L )
Time ( Mins ) Time ( Mins )
Normal
PCOS
Normal
PCOS

23. Insulin Sensitizers
• Mainstay of managing insulin
resistant PCOS is with insulin
sensitizers.
• Commonest drug used is
Metformin.
• Dose of 1500 –1700mg/day in
divided doses.
• Causes G.I. side effects

24. Study : 626 infertile women randomly assigned to
CC+Placebo
Metformin + placebo x 6 months
Metformin + Clomiphene
0
5
10
15
20
25
30
Live Birth rate Multiple pregnancy
22.5%
7.2%
26.8%
6%
0%
3.1%
CONCLUSION
Clomiphene is
superior to
Metformin in
achieving live birth
in infertile women
with PCOS though
multiple birth is a
complication
PPCOS trial (Pregnancy in PCOS Trial)
Ref : Lagro RS et al N. Engl J Med 2007 Feb

25. PPCOS trial
(Pregnancy in PCOS Trial)
Ref : Lagro RS et al N. Engl J Med 2007 Feb

26. Insulin Sensitizers in PCOS
Conclusion :
- Metformin is an effective treatment for
anovulation in women with PCOS
- Ovulation rates higher when combined with CC
- Reduces risk of OHSS by approximately 75%
- ↓ serum E2 levels
Contd…..
Ref : Lord J M, Flight HK et al. Cocherane syst Rev 2005:3

27. Other Insulin Sensitizers
• Rosiglitazone; Piolitazone have been used
but associated weight gain, less favorable
pregnancy profile and possible cardiovascular
risk limit their use for this purpose.
• Inositols
Ref. Cochrane Database Syst. Rev 2010

28. Anovulation

29. BMI
Specific programs
For lifestyle
Modifications (at
least 6 months) in
Obese women
Clomiphene Citrate
Metformin
Metformin+CC
Metformin+
Gonadotropins (?)
LOD
(in infertile PCOS
pts when co-
factors of sub
fertility are
suspected and/or
diagnosed)
Gonadotropins
COS+TI / IUI
ARTs
PREGNANCY
Palomba. Ovulation induction in
PCOS. Fertil Steril 2006
Ovulation Induction in PCOS- Best
Practices
Gh + Gn
Antagon + IUI

30. Gynaecworld Fertility Unit
PCOS COH + IUI cycles = 269
Pregnancy rate based on different stimulation protocols
No. of cycles Positive preg. Success %
CC 46 15 32.6%
CC + Gonadotropins 59 13 22.03%
Only Gonadotropins 61 17 27.87%
CC/ Gn+ Antagon 103 43 41.74%
Mean pregnancy rate = 86/269 = 32.71%
Metformin added to all cycles.

31. ART Results- PCOS v/s Non PCOS
Meta-analysis of 9 observational studies
Ref. Heijnen EM, et.al. Hu. Reprod. Update 12(1), 13-21 (2006)
• 458 women with PCOS - 793 cycles
• 694 matched controls - 1116 cycles
• In PCOS women-
- ↑ cycle cancellation rate
- ↑ risk of OHSS
- ↑ no. of eggs collected
- Lower fertilization rate
- Similar pregnancy rate
- Similar miscarriage rate as non PCOS pts.

32. Gynaecworld Fertility Unit -ART Data
No. of PCOS No. of Non PCOS
Total follicles 910 423
Oocytes recovered 800 360
Mature oocytes 695 (86.87%) 314(87.22%)
Grade 1 Embryos recovered
from Mature oocytes
605 (87.05%) 277 (88.21%)
Total pts. 69 39
Pregnancies 33 18
Pregnancy rates 47.83% 46.15%
Ongoing pregnancy 9.09% 11.11%
Live Birth Rates 75.76% 72.22%
Abortion Rates 6.06% 5.55%
Biochemical pregnancy 6.06% 5.55%
Ectopic pregnancy 3.03% 5.55%

33. Predictive Markers for Ovarian
Response
Ref. Nardo LG, Gelbaya TA et.al. Fertil Steril. 2009 Nov;92 (5): 1586-
93 Epub 2008 Oct 18
FSH, AMH, AFC
• Prospective cohort study
• 165 women - 134 normal responders
15 poor responders
16 high responders
Contd..

34. Ref. Nardo LG, Gelbaya TA et.al. Fertil Steril. 2009 Nov;92 (5): 1586-
93 Epub 2008 Oct 18
AMH levels & AFC levels
• ↑ in high responders
• ↓ in poor responders
• AMH – performed better in the prediction of excessive
response to ovarian stimulation compared to FSH & AFC
AMH to be in corporated into work up protocols to
predict pts. ovarian response to treatment.
Predictive Markers for Ovarian
response

35. Gynaecworld Data
• Total no.of PCOS pts. = 151
LH FAI SIF SIPG
5.7
11.5 11.4
4.9
8.2
15.4
7.9
18.6
29.4
49.3
85.5
132.8
AMH < 6
AMH < 6 - 10
AMH < 10 - 15
0
15
30
45
60
90
120

36. Gynaecworld Experience -PCOS & Predictive
Markers
Mean - values Pregnant Non
Pregnant
P. Value
AMH 4.09 3.17 < 0.0001
LH 12.07 5.18 < 0.0001
BMI 28.10 22.12 < 0.0001
FI 11.46 7.2 < 0.001
PGI 53.65 22.39 < 0.001
Levels prior to Rx.

37. Conclusions
• If obese, weight loss, should be recommended
prior to initiation of therapy.
• Hyperandrogenism, Hyperinsulinemia should be
looked for in every PCOS woman
• Ovulation inducing agents and adjuvants should be
customized.
• Use of Metformin improves pregnancy rates when
added to the ovulation induction protocol
Contd..

38. Conclusions
• Use of Metformin and Antagonist help to
reduce the risk of OHSS following ovulation
induction.
• ART results in PCOS are comparable to non
PCOS pts.
• AMH levels and AFC can serve as predictive
markers for response to COH.

40. International Faculties