gnrh-a to trigger ovulation should be used in all pcos patients to prevent ohss
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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. - PowerPoint PPT PresentationTRANSCRIPT
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 0.02OHSS (PP)
Total, n (%) 0/30 (0) 10/2( 34.5) 0( 0–0.26)a <0.01Moderate/severe, n (%) 0/30 (0) 5/29( 17.2) 0 (0–0.73)a 0.02Secondary end point (PP)
Implantation rate, n (%) 22/61( 36) 20/64( 31) 1.18( 0.52–2.65) 0.69Other end points (PP)
Positive pregnancy, n (%) 19/30( 63.3) 18/29( 62.1) 1.06( 0.37–3.0) 0.92Clinical pregnancy rate, n (%) 17/30( 56.7) 15/29( 51.7) 1.22( 0.4–3.4) 0.45Ongoing 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 ±2.0GnRH antagonist (days) 3.8 ±0.9FSH (units) 2443 ±925E2 day of trigger (pmol/L) 3764 ±1227P day of trigger (nmol/L) 2.4 ±1.65LH day of trigger (IU/L) 1.9 ±1.3Oocytes 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 ± 86E2 (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