GnRH-a to trigger ovulation should be used in all PCOS patients to prevent OHSS

Dr. Shahar Kol

Disclaimer

• The following presentation reflects my own experience and opinion.

• The presentation does not necessarily reflect drug companies’ policies.

• I mention off-label use of medications, this use is not endorsed by drug companies.

IVM

• This option is thoroughly discussed in this meeting.

• If you adopt IVM you need not worry about OHSS.

• If you choose to stimulate your PCOS patient, please use the GnRH antagonist option.

• Mild stimulation is a great idea, not easy to implement.

AUGUST 2009 VOL 5 NO 8AUGUST 2009 VOL 5 NO 8

AUGUST 2009 

AUGUST 2009 VOL 5 NO 8

If you choose a long GnRH agonist protocol, this what might happen

Basic clinical details

• 25-year-old, 2 years of primary infertility• Irregular cycles, facial hair• BMI=24, LH=14.9, Testo=2.5, FSH-normal• US: PCOS• Impaired glucose tolerance – started

Metformin 850 twice daily• Sperm-normal• FSH-normal

Pre-IVF treatment

• CC up to 100 mg daily – no ovulation• 5 cycles with recFSH 50 U daily. Four cycles

mono-ovulation, 1 cycle cancelled for multifollicular development. No pregnancy.

• Referral to IVF.

IVF – cycle I

• Long agonist protocol, continue metformin, daily gonadotropin dose of 112.5 U – no response, increase to 150 U – good response

• Trigger with hCG 10,000 U• OPU: 16 eggs from 20 follicles.• ET: 2 embryos, no pregnancy.

IVF-cycle II

• Same long protocol, continue metformin, starting dose 150 U.

• After 7 days: “unfortunately” 25 follicles<12 mm, 9 follicles 13-16 mm, dose reduced to 125 U, trigger with hCG 5,000 U.

• OPU: 41 eggs, 21 embryos frozen.• 2 days later: abdominal pain, vomiting.• US: large ovaries.• Hemoglobin -16.3, WBC-31,700. • Decision to hospitalize.

In hospital

• IV fluid (crystaloid), enoxaparin 40mg• Poor urinary output, albumin i.v• Fluid balance +1,500 in 24 h.• Chest X-ray: pleural effusion

Getting worse

• Chest and abdominal drains.• During 24h 2 L of ascitic fluid and 1 L pleuritic

fluid was drained.• Further deterioration: O2 sat <95%, X-ray:

bilateral pleural effusion and pulmonary edema.

ICU

• Risk of adult RDS – transferred to ICU• 2nd chest tube inserted• Central i.v. line• Continue albumin• Gradual improvement and discharge after a

few days.

Severe OHSS: is it still a problem?

• “In 2003–2005, 4 deaths (of the 12) were due to OHSS”

• ~3 OHSS-related deaths per 100,000 ART cycles

Year

Deaths

95% CI

Number of treatment

cycles Number Rate

1997 –1999 20 19.17 12.41–29.61 104,320

2000–2002 8 7.32 3.71–14.44 109,308

2003–2005 12 10.08 5.76–17.61 119,080

* Source Human Fertilisation and Embryology Authority

Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005

Three OHSS-related deaths (3:100,000), all had their embryos frozen

Braat DDM, et al. Hum Reprod 2010;25:1782–1786

Youssef MA, et al. Human Reprod Update 2010;16:459–466

What really works:

● GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles

OHSS % (n) n Ovulation trigger

Oocyte source

Trial type Reference

0 (0/13)31(4/13)

1513

GnRHahCG

Own RCT, high risk Babayof, et al 2006

0 (0/33)31 (10/32)

3332

GnRHahCG

Own RCT, high risk Engamnn, et al 2008

0 (0/30)17 (5/30)

3030

GnRHahCG

Donors RCT Acevedo, et al 2006

0 (0/1046)1.3 (13/1031)

10461031

GnRHahCG

Donors Retrospective Bodri, et al 2009

0 (0/40) 40GnRHa Own Observational,

High riskGriesinger, et al 2010

0 (0/152)2 (3/150)

152150

GnRHahCG

Own RCT Humaidan, et al 2009

0 (0/23)4 (1/23)

2323

GnRHahCG

Own Retrospective, case-controlled, high risk

Engmann, et al 2006

0 (0/42) 42GnRHahCG - cancelled

Own Retrospective case-control, high risk

Manzanares, et al 2009

0 (0/254)6 (10/175)

254175

GnRHahCG

Donors Retrospective Hernandez, et al 2009

0 (0/82)7 (5/69)

8269

GnRHahCG

Own Retrospective, high risk

Orvieto, et al 2006

0 (0/32)1 (1/42)

3242

GnRHahCG

Donors Retrospective, high risk: agonist arm only

Shapiro, et al 2007

0 (0/44)7 (3/44)

4444

GnRHahCG

Donors RCT Sismanoglu, et al 2009

8 (1/12) 12GnRH, luteal rescue with hCG 1500IU

Own Observational, high risk

Humaidan, et al 2009

0 (0/106)8 (9/106)

106106

GnRHahCG

Donors RCT Galindo, et al 2009

0 (0/50)16(8/50)

5050

GnRHahCG

Donors RCT Melo, et al 2009

0 (0/45)15 (33)

445

GnRHahCG

Own RCT, high risk Shahrokh, et al 2010

• 16 publications

• Agonist: 2005 patients, not a single case of OHSS!

• hCG: 92 cases in 1810 patients, 5.1%

The physiology of agonist trigger

1. Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print);2. Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922

LH surge1 FSH surge2

What happens after agonist trigger? Complete luteolysis!

Luteal phase

Natural cycle Day 7–9 = 75 pg/mL vs 18

Natural cycle Day 7–9 = 750 pg/mL vs 84

Nevo O, et al. Fertil Steril 2003;79:1123–1128

“The concept of an OHSS-Free Clinic has become a reality. This approach should include pituitary down-regulation using a GnRH antagonist, ovulation triggering with a GnRH agonist and vitrification of oocytes or embryos”

“…luteal phase supplementation with low-dose hCG has to be fine tuned.”

Devroey P, et al. Human Reprod 2011; 26: 2593–2597

OHSS prevention by GnRH agonist triggering of final oocyte maturation in a GnRH antagonist protocol in combination with freeze-all strategy: a prospective multicenter study

• Conclusions: “…a single case of a severe early onset OHSS occurred”

– E2 trigger day=47,877 pmol/L– 13 oocytes– The patient was hospitalized on day of OPU, with abdominal distension,

drastically enlarged ovaries (right and left ovarian volume 363 cm2 and 261 cm2, respectively), and lower abdominal pain.

– She received low molecular weight heparin, cabergoline (0.5 mg/d), and IV infusion therapy, including albumin.

Griesinger G, et al. Fertil Steril 2011;95:2029–2033

Failures?

Failures? (cnt’d)

– “drastic decrease of hemoglobin levels to 4.9 mmol/L” (8 grams/dL) patient received blood transfusion 2 days post OPU.

– Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post blood transfusion.

– 3–4 days post trigger 3.9 litres of “blood-stained ascites which was indicative of a subacute intraperitoneal hemorrhage”.

How to secure good clinical outcome post agonist trigger?

• High risk fresh transfer: intensive E2+P luteal support

• High risk: ‘freeze-all’• Low risk: luteal rescue based on LH activity

Luteal phase: intensive E+POHSS high-risk patients

Study group Control group Odds ratio (95%CI) p value

Primary end points

OHSS (ITT)

Total, n (%) 0/33( 0) 10/32( 31.3) 0( 0–0.26)a <0.01Moderate/severe, n (%) 0/33 (0) 5/32( 15.6) 0 (0–0.74)a 0.02

OHSS (PP)

Total, n (%) 0/30 (0) 10/2( 34.5) 0( 0–0.26)a <0.01

Moderate/severe, n (%) 0/30 (0) 5/29( 17.2) 0 (0–0.73)a 0.02

Secondary end point (PP)

Implantation rate, n (%) 22/61( 36) 20/64( 31) 1.18( 0.52–2.65) 0.69

Other end points (PP)

Positive pregnancy, n (%) 19/30( 63.3) 18/29( 62.1) 1.06( 0.37–3.0) 0.92

Clinical pregnancy rate, n (%) 17/30( 56.7) 15/29( 51.7) 1.22( 0.4–3.4) 0.45

Ongoing pregnancy rate, n (%) 16/30( 53.3) 14/29( 48.3) 1.22( 0.4–3.4) 0.45aThe estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat; PP=per protocol

Engmann L, et al. Fertil Steril 2008;89:84–91

GnRHa Trigger and Total Freeze in High Risk Patients

Griesinger et al., 2007, observational, 20 high- risk patients (≥ 20 follicles ≥ 11mm)

- cumulative ongoing pregnancy rate 37%

Griesinger at al., 2011, observational, 51 high-risk patients (≥ 20 follicles ≥ 11mm)

- cumulative live bith rate 37%

The advantage for the ‘normal responder’

Kol S, et al. Human Reprod 2011;26:2874–2877

FSH/hMG

AntagonistAgonist trigger

36 hours

OPU

1500 IU hCG

4 days

1500 IU hCG

ET

Stimulation characteristics and embryology data

Stimulation (days) 9.3 ±2.0

GnRH antagonist (days) 3.8 ±0.9

FSH (units) 2443 ±925

E2 day of trigger (pmol/L) 3764 ±1227

P day of trigger (nmol/L) 2.4 ±1.65

LH day of trigger (IU/L) 1.9 ±1.3

Oocytes retrieved 6.7 ±2.5

Embryos obtained 3.6 ± 1.7

Embryos transferred 2.9 ± 0.9

Embryos frozen 0.8 ± 1.5

Beta hCG (IU/L) 152 ± 86

E2 (day of pregnancy test, pmol/L) 6607 ± 3789

P (day of pregnancy test, nmol/L) 182 ± 50Values are mean ± SD

Reproductive outcomes

Positive hCG/cycle, n (%) 11/15( 73)

Clinical ongoing pregnancy, n (%) 7/15( 47)

Early pregnancy loss, n (%) 4/11( 36)

Kol S, et al. Human Reprod 2011;26:2874–2877

Side benefits

• Agonist trigger: more MII oocytes compared with hCG trigger1-4

• Potential benefit of FSH surge:5-9 – Promotes LH receptor formation in luteinizing

granulosa cells– Promotes nuclear maturation (i.e. resumption of

meiosis) – Promotes cumulus expansion

1. Humaidan P, et al. Reprod Biomed Online 2005;11:679–6842. Humaidan P, et al. Human Reprod 2009;24:2389–23943. Imoedemhe DA, et al. Fertil Steril 1991;55:328–3324. Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5. Eppig JJ. Nature 1979;281:483–4846. Strickland and Beers. J Biol Chem 1976;251:5694–57027. Yding Andersen C. Reprod Biomed Online 2002;5:232–2398. Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–7319. Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

Anecdotal cases

• You may consider GnRH agonist trigger in the following cases:– Repeated IVF failure– “empty follicles” syndrome– Immature oocytes despite adequate follicular

diameter

Crystal ball: where are we heading?

Out In‘Long agonist’ protocols Antagonist-based protocols

hCG trigger Agonist trigger

1–2% severe OHSS Total OHSS elimination

OHSS-related death rate: 3:100,000 Total OHSS elimination