IVF in PCOS Aboubakr Elnashar Benha University Hospital, Egypt

1. IVF in
PCOS
Aboubakr
Elnashar
Benha University
Hospital, Egypt
ABOUBAKR ELNASHAR

2. CONTENTS
 Introduction
 Prevalence
 Indications
 Patient preparation
 Gonadotropin and protocol choices
 Monitoring and trigerring of ovulation
 ET
 Luteal phase support
 Prevention of OHSS
 Outcome
 IVM
 Conclusion
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3.  PCOS:
 most common disorder in women of reproductive age
 Primary cause of anovulatory infertility.
 No clear consensus on its specific definition.
 All of the diagnostic criteria include some combination of
oligo-anovulation
androgen excess and
PCO.
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4.  NI (1990)
 Chronic anovulation.
 Cl and/or biochemical
hyperandrogenism.
Rotterdam (2003)
2 out of 3
 Ch anovulation.
 Cl and/or biochemical
hyperandrogenism.
 PCO on US
AES (2006)
AE-PCOS(2009)
 Cl and/or biochemical
hyperandrogenism.
 Ovarian dysfunction
(anovulation and/or PCO)
 Exclusion of related ovulatory or other androgen excess disorders (e.g.,
thyroid dysfunction, hyperprolactinemia, androgen-secreting neoplasms, or non
classic adrenal hyperplasia)
8% 18% 12%
Prevalence of PCOS
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5.  Reinforced the use of Rotterdam Criteria to
diagnose PCOS.
 Recommended 4 phenotypes of PCOS.
1. Hyperandrogenism + ch anovulation (H-CA).
2. Hyperandrogenism + PCO (H-PCO).
3. Ch anovulation + PCO (PCO-CA).
4. Hyperandrogenism + ch anovulation + PCO
(HCA-PCO).
Evidence-Based
Methodology
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6. Four different phenotypes of PCOS based on Rotterdam
Criteria
PCOS
phenotypes
Oligo or
anovulation
Biochemical or
clinical
manifestations of
hyperandrogemia
PCO in
TVS
1-Severe PCOS + + +
2-Oligo- or
anovulation and
hyperandrogenemia
+ + -
3-Ovulatory
PCOS
- + +
4-Mild PCO + - +
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7. PCOS is associated with a range of reproductive,
obstetric, and metabolic features.
 Reproductive manifestations:
hyperandrogenism, menstrual dysfunction,
anovulation, and PCO on ultrasound.
 Obstetric manifestations: early pregnancy loss,
gestational diabetes, and pregnancy-induced
hypertension.
 Metabolic manifestations: obesity, insulin
resistance, IGT, DM , and metabolic syndrome.
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8. Reproductive manifestations
1.Hyperandrogenism
 Hirsutism: 60% of PCOS.
 Acne: 30% of PCOS.
 Androgenic alopecia.
 Menstrual irregularity {anovulation}
 Ovulatory dysfunction: oligoamenorrhea: 80%
 Definition of ch anovulation in PCOS is based on:
 Exclusion of other causes of anovulation.
 Measurement of midluteal progesterone.
 Absence of corpus luteum by TVS.
2. Ovulatory and menstrual dysfunction
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9. PCO on ultrasound
Criteria of polycystic ovarian morphology
12 or more follicles, 2 - 9
mm in diameter and/or
Ovarian volume >10 cm3.
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10. ABOUBAKR ELNASHAR

11. Weight reduction
Oral anti-estrogens (CC)
Obese &overweight
Normal weight &No weight loss & No ovulation
LODGnT
No ovulation after 3 cycles.
No pregnancy after 6 cycles.
No pregnancy
after 6 cycles.
No pregnancy after spontaneous,
CC, FSH ovulation
IVF
Other surgical indication
Difficult follow up
Less aggressive
No desire for
surgery
Add metformin
IGT &IR
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12. Causes of chronic anovulation in PCOS
1-Relative FSH deficiency
2-Hypersecretions of:
-LH
-Insulin
-Estrogen
-Androgen
-Inhibin B
3-Attenuated apoptosis.
4-Aberrant expression of growth factors.
5-Abnormalities in ovarian steroid production.
-Theca cells hyper secrete androgens
-Granulosa cells have increased
aromatase activity
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13. PREVALENCE
33% of women attending for IVF had PCO.
(MacDougall et al. 1993).
PCO occur in 20–30% of IVF Patients
(Sherif, 2012)
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14. INDICATIONS
IVF is not 1st line of tt in PCOS.
1-Other factors: tubal factor, male factor 50% of
subjects had other factors.
(Tannys, 2010)
2. Failure to conceive despite at least 6 ovulatory
cycles
(Adam, 2007).
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15. 
1. Failure to conceive on Gnt therapy alone/ IUI
(Araki, 2011)
2. Failure of wt reduction, antiestrogen therapy or
LOD, it may be argued that induction of ovulation
with Gnt should be omitted and replaced by
ovarian stimulation and IVF.
(Eijkemans et al., 2005)
3. High response to FSH (4 or more follicles)
despite low Gnt dose.
4. To eliminate the chances of MP particularly for
some older women: single ET
(Papanikolaou et al., 2006;Heijnen et al., 2007)ABOUBAKR ELNASHAR

16. PATIENT PREPARATION
I. Counseling & information: How pregnancy occur
Indication, steps, PR, problems, Financial
II. Evaluation
1. General: history, Gyn Exam, Screen for Hepatitis, DM,
2. Semen analysis
3. ORT
4. Hormonal:
5. TVS.
6. Hysteroscopy??
III. Management of associated conditions: Habits, Obesity,
DM
IV. Preventive treatment.
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17. I. Counseling and information
 increased obstetric risk (gestational diabetes, PET and
fetal morbidity) if overweight.
 Potential problems as OHSS and multiple pregnancy.
II. Evaluation:
Screen for DM
III. TT of associated condition:
Cessation of smoking, Weight reduction
IV. Preventive TT:
Doxycyclin: 100mg 1x2x7d., Diflucan or Flucoral one caps.
Flagentyl 4 tablet
Folic acid 0.5mg. Aspirin 75mg /day are continued
Prevention of OHSS in PCOS:
Metformin: given in the period prior to ART
LOD
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18. CHOICE OF GONADOTROPINS
Type:
No difference in outcome between ovarian
stimulation with hMG preparations or urinary derived
FSH, in studies using the long protocol of GnRH
desensitization.
(MA: Agrawal et al. 2000)
No significant clinical differences between hMG
and rFSH.
(Nugent et al., Cochrane Data base Syst Rev 2000; van Wely et al, 2003)
hMG, uFSH, and r-FSH: equally effective for
achieving pregnancy in PCOS.
(Al-lnany et al.,2005)
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19. STIMULATION PROTOCOLS
GNt dose:
low dose in either a long protocol, or short GnRHa
protocol
50–150 IU
depending on age and other factors
Protocols
1-GnRHa
(Griesinger et al., 2006)
2-GnRHan
(Griesinger et al., 2006)
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20. Short protocol
should not be proposed
{initial flare-up effect could lead to an excessive
ovarian response}.
Metformin
{reduce risk of OHSS}
(dose 850mg twice daily from the start of
down-regulation to the day of oocyte retrieval).
History of severe OHSS
GnRHan and use a single-shot of agonists for final
oocyte maturation.
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21. GnRHan Vs GnRHa protocol
Effective
Shorter duration of Gnt stimulation.
Lower total dose of Gnt.
Improved patient acceptance
interventions to prevent OHSS (e.g. coasting,
cycle cancellation) less
(European Orgalutran Study Group 2000 ; North American Ganirelix Study
Group 2001; Schultzer Mosgau et al , 2005)
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22. MONITORING RESPONSE TO STIMULATION
US and E2
1. US: Evaluate whether the dose of GnT is adequate or
not.
1st US
 D4 Stimulation
In PCO
 D 5 or 6 stimulation
In normal responder
Number: 6-8 each ovary
 With diameter: 11- 12 mm ABOUBAKR ELNASHAR

23. US in day of HCG
 High risk of OHSS
 Number of follicles >20
 Number of small & intermediate size (10-14 mm)
>15
 No risk of OHSS
 immature follicles are < 15.
{Number of the immature follicles is more important
than the number of mature follicles in predicting
OHSS.
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24. 2. E2:
Level:
<1000 pg/ml: No OHSS
>3000-4000 pg/ml: HCG should be withheld
<3500 pg/mL: No OHSS (Asch et al 2005)
3500-5999 pg/mL: 1.5%
6000 pg/mL: 38%
Slope:
Cases with severe OHSS are seen with E2 <1500
pg/ml.
slope of rise of E2 is more accurate (considered if
the value is doubled).
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25. Do not trigger ovulation with the intention of fresh
ET in women who have:
E2>3500 pg/ml or
>20 follicles on US
(NICE, 2013)
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26. HOW TO TRİGGER THE OVULATİON
1.Decrease HCG dose:
As low as 3300 IU
as low as 2500 IU is effective in PCOS.
(Kashyap et al.,2010)
2000 IU: ineffective, lower successful oocyte recovery
(Kashyab et al, 2010).
does not prevent OHSS
(Kol, Dor, 2009)
There is no clear published evidence that lowering HCG
dose will result in a decrease in the rate of OHSS. (III)
2-GnRHa trigger
-0% incidence of OHSS
(Humaidan et al.,2011) ABOUBAKR ELNASHAR

27. EMBRYO TRANSFER
Maximum of 2 embryos: reduces MPR
Single ET
Young women significantly reducing MPR
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28. LUTEAL PHASE SUPPORT
 HCG
2-fold increase in OHSS than tt with progesterone
alone
(Daya, Gunby, Cochrane Database 2004)
Progesterone
-No superiority of IM progesterone over vaginal
(Zarutskie and Phillips, 2009; Fatemi,2009; Mitwally et al., 2010)
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29. Triggered by agonist
a. Intensive progesterone and estradiol
b. Single bolus of hCG (1500 IU) on the day of OPU in
addition to a standard LPS with vaginal progesterone
and oral E2.
(Humaidan et al., 2006, 2009; 2010)
c. Repeated boluses of hCG (500 IU) 3 doses started
on the day after OPU with every 3rd day (OR + 1, OR
+ 4 and OR + 7).
d. Repeated doses of Rec LH
-6 alternate doses of 300 IU rLH were
administered starting on the day of OR
and repeated on days OR + 2, OR + 4,
OR+6, OR + 8 and OR + 10.ABOUBAKR ELNASHAR

30. PREVENTION OF OHSS
The incidence of severe OHSS:
significantly higher in PCOS (15%) compared with
normal ovaries (3%).
(Swanton et al., 2010)
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31. Primary prevention
1. Prediction of OHSS from history, exam, and US
2. LOD in PCOS
3. Metformin in PCOS
5. Low-dose Gnt in PCOS
6. GnRHan protocol
7. Rec LH to trigger ovulation
8. GnRHa to trigger ovulation
9. IVM of oocytes
10. Replacement of only one embryo
(Rizk B., 2006) ABOUBAKR ELNASHAR

32. 2ndry prevention
1. Withholding hCG ± continuation of GnRHa/GnRHan
2. Coasting or delaying hCG: currently most popular method
3. Use of GnRHa to trigger ovulation
4. Follicular aspiration
5. Cryopreservation and replacement of frozen–
thawed embryos at a subsequent cycle
6. Progesterone for luteal phase
7. Dopamine agonist
8. Albumin: administration at time of retrieval
9. Glucocorticoid administration
10. Aromatase inhibitors
Rizk (2006)
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33. Cancelling hCG
-It is usually reserved for patients at high risk cases
-Presence of several risk factors
-Patients with total loss of cycle control
(Delvigne and Rozenberg; 2002)
Cryopreservation of oocytes and embryos
: higher cumulative PR than coasting to avoid
OHSS.
(Sills et al., 2008; Fitzmaurice et al., 2008.; Gera et al., 2010).
Can be applied when GnRHa triggering
rec hCG instead of urinary hCG
No statistically significant difference
(Al-Inany, Cochrane Database 2005; Kashyap S et al., Semin Reprod
Med 2010)
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34. Coasting
-no evidence to suggest a benefit of coasting to
prevent OHSS compared with no coasting or other
interventions.
(D'AngeloA et al., Cochrane Database Syst Rev 2011)
Use of dopamine agonist from the day of hCG
trigger
-Women with PCOS are less responsive to
cabergoline compared with those without PCOS.
(Gomez R et al., 2011; Manzanares et al., 2010)
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35. Hydroxyethyl starch (HES)
a significant reduction in the incidence of OHSS
without affecting PR.
(Jee BC et al., 2010)
In vitro maturation of oocytes (IVM)
-It avoids exogenous Gnt (avoiding the risk of
OHSS)
-IVM may be a promising alternative to conventional
IVF.
(Child et al., 2002)
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36. OUTCOME OF IVF IN PCOS
PCOS or isolated PCO-only morphology
Behave exactly in the same manner during all stages
of ART
Response to ovarian stimulation:
better than that for women with normal ovaries
Cycle cancellation rate:
significantly increased in PCOS (12.8 Vs 4.1%).
Duration of stimulation:
significantly longer in PCOS (1.2 days), even when
the daily dose of FSH is similar to that of women
without PCOS. ABOUBAKR ELNASHAR

37. Retrieval Cumulus–oocyte complexes:
Significantly more in women with PCOS
Fertilization rates
similar as compared with women without PCOS.
(MA: Heijnen et al., 2006)
CPR/ET:
Higher compared with isolated male factor infertility.
(Esinler et al.,2005)
Outcome of pregnancy:
similar.
(Esmailzadeh et al., 2005)
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38. IVM
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39. IVF vs IVM in PCOS
 No RCT:
 The number of mature oocytes
No significant difference
(Shavit et al, 2014)
 The average dose of gonadotropin, fertilization rate
and high-quality embryo rate:
significantly higher in the GnRHan group compared with
the IVM group.
 PR, LBR/pregnancy and abortion rates:
comparable.
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40. CONCLUSIONS
 PCOS patient is the most difficult to treat with IVF
 Cycle cancellation rates and risk of OHSS are
higher
 PR in women with and without PCOS are similar,
this suggests that implantation is not compromised
in PCOS.
 Fine tailoring of ovarian stimulation is necessary to
avoid complications
 hMG, uFSH, and r-FSH are equally effective for
achieving pregnancy in PCOS.
 Antagonist protocol with GnRHa triggering is
associated with a very low risk of OHSS.
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41. Thanks
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