IVF in

PCOS Aboubakr

Elnashar Benha University

Hospital, Egypt

ABOUBAKR ELNASHAR

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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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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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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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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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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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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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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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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Weight reduction

Oral anti-estrogens (CC)

Obese &overweight

Normal weight &No weight loss & No ovulation

LOD GnT

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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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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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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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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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)

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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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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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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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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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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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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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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

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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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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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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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)

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EMBRYO TRANSFER

Maximum of 2 embryos: reduces MPR

Single ET

Young women significantly reducing MPR

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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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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.

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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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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

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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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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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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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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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.

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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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IVM

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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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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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Thanks

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