Stimulating PCOS Patients

Undergoing IVF

Peter Casson MD

Reproductive Endocrinologyand Infertility

Northeastern Reproductive MedicineColchester, Vermont

Definition of PCOS

PCOS: Causes and

PrevalenceGenetic

Steroid biosynthetic enzymes

Androgen receptor

Insulin receptor

Associated with Family history of NIDDM

Insulin resistance (50%)

Obesity

Prevalence increasing 10-20% of women of

reproductive age

30% of infertile patients

PCOS: Traditional Ovulation

Induction Getting better but not perfect (Legro, NEJM, 2014)

Predictors of failure:

BMI

Hyperinsulinemia

High AMH

Hyperandrogenemia

Letrozole

Clomiphene

Reasons to Move On To IVF

in PCOS Patients

Failed ovulation

Ovulation but no pregnancy ( usually after IUI)

Advancing reproductive age

Other concurrent infertility factors

Concurrent PGS/PGD

Prevalence OF PCOS in IVF

0

2

4

6

8

10

12

14

16

2005 2006 2007 2008 2009 2010 2011 2012 2013

Ovulatory dysfunction (%)

CDC SART Data

IVF Stimulation in PCOS

Patients: Problems Tough to monitor

Overly vigorous stimulations

Tough retrievals

Variable oocyte quality

? Decreased fertilization rate

OHSS

Strategies to Improve IVF

Stimulations/Outcomes in PCOS

Patients

Metformin

ICSI

IVM

Coasting

Cabergoline

Antagonist cycles

Agonist trigger

Freeze all cycles

Agonist trigger/freeze all cycle

ARS Question 1

I use metformin as an adjunct to IVF in

PCOS patients:

a. in all PCOS patients

b. in lean PCOS patients

c. when there is evidence of

hyperinsulinemia

d. only if the patient has failed a previous

IVF cycle

Metformin: Evidence for a Beneficial

Effect in Ovulation Induction

Small RCTs in POCS patient undergoing hMG ovulation induction

Decreased OHSS, multiple pregnancy, hMG utilization• Yarali Hum Reprod 17(2) 2002

• Tadesmir Arch Gynecol Obstet 269, 2004

Increases mono-ovulatory follicle development• Palomba Hum Reprod 20(10), 2005

Decreased miscarriage rate

Two non-randomized studies demonstrate >50% decrease in first trimester miscarriage in PCO patients

• Jakubowitz JCEM 87(2), 2002

• Glueck, Fertil Steril 75, 2001

PPCOS I: Metformin is Not as

Effective as Clomiphene

P-value: <0.001

ClomipheneMetforminCombined

Rate of Live Birth

0.0

0.1

0.2

0.3

0.4

0.5

Days from Randomization to Live Birth150 200 250 300 350 400 450 500

Legro, NEJM, 2007

Meta analysis of 9 RCTs

Clinical pregnancy rate higher (OR 1.52, 1.07 to 2.15)

70 % reduction in OHSS (OR 0.29, 0.18 to 0.49)• Tso, Cochrane Database Syst Rev 2014

• Tso Fertil Steril, Sept 2015

Metformin in PCOS/IVF

Metformin in POCS/IVF

WHO Guidelines:

“Metfomin useful to reduce the risk of OHSS”• Balen, Hum Reprod Update August 2016

BFS Guidelines:

“has a positive effect in women with PCOS undergoing IVF”

• Nardo, Hum Fertil 18(1) 2015

SOGC Guideline:

“The addition of metformin should be considered in patients with PCOS undergoing IVF because it may reduce the incidence of OHSS”

• SOGC guideline 315, November 2014

Possible indications for

Metformin use in PCOS/IVF

Indications:

Multiple pregnancy losses

Poor oocyte quality/failed cycle

Lean PCOS

Evidence of insulin resistance

OR

Anyone with clinically diagnosed PCOS

ARS Question 2

I use ICSI in PCOS cycles:

a. in all PCOS/IVF cycles

b. in nulligravid PCOS patients only

c. only when there is concurrent

hyperinsulinemia

d. only when other concurrent indications

for ICSI exist (male factor, failed

fertilization, PGS/PGD)

ICSI in PCO/IVF

Fertilization rate reported lower in patients with PCOS at IVF

Sibling oocyte study (PCO, normal sperm)

1089 oocytes from 60 cycles randomized to ICSI or standard IVF

Higher fertilization rate (72% vs. 45%), lower total fertilization failure (0% vs. 15%)

• Hwang, Hum Reprod 20(5), 2005

No Randomized controlled trials

ICSI Use 2004-2013

SART CDC 201336% to 76% of all IVF cycles from 1996 to 2013

Is ISCI Overused? SART CDC Data

ICSI/Unexplained infertility (n = 317 996)

Lower implantation (23.0% vs 25.2%, RR, 0.93; 95%, 0.91-0.95)

Lower live birth (36.5% vs 39.2%, RR, 0.95; 95% CI, 0.93-0.97)

Boulet JAMA, 313(3), 2015

ICSI in PCOS/IVF:

Recommendation

Use ICSI only if clear indication

Male

Previous failed/suboptimal fertilization

PGS/PGD

? Less than 4 oocytes

OR

Split cycles to see which is better in your lab

ARS Question 3To reduce the risk of hyper stimulation in PCOS

patients being stimulated for IVF, I use:

a. coasting

b. In Vitro maturation

c. low dose hCG trigger (+/-cabergoline)

d. lupron trigger and freeze all

IVM at IVF

Retrieval of immature (GV) oocyte-cumulus complexes from follicles <13 mm with or without a short course of rFSH or hCG priming

In vitro culture with added hCG, FSH for up to 3 days

Used in patients at risk for OHSS and fertility preservation

Faster, less expensive, works best in PCOS patients

No OHSS

Lower pregnancy rates than standard IVF

IVM Exists on a Continuum

ICSI of Immature GV and MI oocytes that matured in vitro on day 1 or 2

Recovery and IVM of immature oocytes in a early–triggered PCO/IVF cycle

Traditional IVM

IVM in PCOS: Conclusions

Requires special expertise

Effective in reducing OHSS but pregnancy rates are lower

Largely superseded by other techniques to avoid OHSS

Variations of IVM may still be useful to maximize embryo yield from immature oocytes obtained at a PCO/IVF retrieval

Coasting

First described by Sher 199

Withholding gonadotropins/hCGtrigger until E2 falls below a threshold level (3,000-5000 pg/ml)

Larger follicles have less FSH requirement, leads to atresia of smaller follicles, less VEGF production

Need to push stimulation until follicles >12-15 mm

Coasting: Results

Oocyte numbers, fertilization, embryo

development and pregnancy rates not

adversely affected

OHSS rate reduced to 2.5%• Delvigne A, Hum Reprod 16:2491, 2001

Coasting has adverse effect if > 3 days• Mansour R Hum Reprod 20, 2005

Stimulation Tricks That Don’t Work

to Reduce the Incidence of OHSS

rFSH vs hMG

hCG vs rLH

10,000 vs 5,000 IU hCG trigger

Cabergoline For OHSS

Dopamine agonists decrease VEGF

production of granulosa cells in Vitro • Ferrero Repro Bio endocr 2015

60-70% reduction in mild and moderate

OHSS• Cochrane 2012 (2 RCTs)

Meta analysis of 7 studies, 858 women:

60% reduction in moderate and severe

OHSS• Leitao Fert Steril 2014

No reduction of pregnancy rate in either analysis

Cabergoline to Prevent OHSS:

0.25 to 0.5 mg daily for 8 days to 3 weeks

Starting at hCG trigger or oocyte retrieval

Often given in conjunction with albumin at retrieval

Done with freeze all or through the first week of

pregnancy

Antagonist Protocols For OHSS

Prevention

Meta analysis of 29 RCTs

Antagonist cycles reduce the risk of OHSS (OR 0.43, 0.33-

0.57)

No difference in pregnancy and live birth• Al-Inany HG Cochrane Database Syst Review 111(5) 2011

Allows for the use of an agonist trigger

Agonist trigger

Pulse of agonist displaces antagonist off GnRH receptors, stimulates endogenous surge of LH/FSH

3-5 mg leuprolide or 0.2 to 0.5mg leuprelin/triptorlin/buserelin 36-40 and again 24 -26 hours before retrieval

Meta analysis of 17 RCTs:

Reduction of OHSS (OR 0.15, 0.05-0.47)

Reduction in live birth rate (OR 0.47, 0.31-0.70)

Higher miscarriage rate (OR 1.74, 1.1-2.75)

No change in pregnancy rate in donor-recipient cyclesYouseff M, Cochrane database syst rev Oct 2014

Agonist Trigger Problems

Lower pregnancy rates in fresh autologous cycles

Freeze all

Intensive luteal supplementation

E, P, supplemental hCG at retrieval or in luteal phase

2% failure rate- no eggs!

Risk factors: prolonged OCP use, hypothalamic anovulation

Check LH, progesterone day after trigger

retrigger if LH <15, reassuring if LH >50

hCG co-trigger (1000-5000 iu hCG)

Freeze all For OHSS Prevention

Demonstrated in 1999 RCT that elective freeze all in at-

risk patients reduced OHSS risk, no difference in

pregnancy rates• Ferraretti, Hum Rep 1999

Problems:

FET rates typically not as high as fresh ETs

Added cost (financial and emotional)

More time commitment

Can still see severe OHSS with no embryo transfer (ie donor

cycles)

Freeze All Vs. Fresh ET in PCOS IVF

Chen et al, NEJM 375(6), 2016

RCT of 1508 PCO patients undergoing IVF (+/- ICSI)

Agonist Stimulation, hCG trigger (4000-8000 IU)

IM Progesterone 80 mg/day for luteal support

Fresh or Frozen ET of 1or 2 day three embryos

Primary outcome live birth

Secondary outcomes:

Clinical pregnancy

Pregnancy loss

OHSS

Intent to treat analysis

Fresh Vs. Freeze All in PCOS/IVF:

Results

Fresh Transfer

(762)

Freeze All

(746)

P Value

Live Birth 42% 49.3% 0.004

Clinical

Pregnancy

56.2% 58.7% 0.32

Loss Rate 25% 14.6% <0.001

Birth Weight,

gr. (singleton)

3349 +/- 553 3511+/-594 0.005

Mod or Severe

OHSS

7.1% 1.3% <0.001

Preeclampsia 1.4% 4.4% 0.009

Chen, NEJM 375(6), 2016

Agonist trigger/Freeze all in PCO

Pros:

Avoid hyperstimulation

Get more eggs

Accrue benefits of FET:

Reduced prematurity, birth defects

Cons:

Can only do if your FET as good as your fresh rate

Additional cost, time, expense

More meds

Optimizing PCOS/IVF Stimulations Metformin reduces OHSS (may improve preg rate)

ICSI not needed (individualize)

Changing gonadotropin, decreasing hCG trigger

has no clear benefit

IVM may help, but requires special expertise

Coasting reduces but does not eliminate OHSS

Cabergoline likely reduces OHSS 60%

antagonist cycles reduce OHSS 50 %

Agonist triggers reduce OHSS 80%

Freeze-all cycles reduce but does not preclude

OHSS

Agonist trigger/freeze all cycles most effective

modality