Ovarian hyperstimulation syndrome (OHSS)

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1 Ovarian hyperstimulation syndrome (OHSS)

2 OHSS OHSS: exaggerated response to gonadotropins and hcg Characterized by: ovarian enlargement increased vascular permeability fluid accumulation in abdomen Associated with: pleural effusion, ascites, hemoconcentration, thromboembolism (rarely) Severe OHSS in 0.8% of stimulated cycles (Europe, 2006) 1 Estimated mortality rate in IVF/ICSI cycles: 3:100, de Mouzon et al. Hum Reprod 2010;25: Braat et al., 2010

3 Symptoms of OHSS Main symptom: abdominal pain Severe cases: vomiting, shortness of breath, fainting and reduced urine Serious illness Abdominal pain accompanied by Rapid weight gain Tense ascites Breathing difficulties Hemoconcentration Hypotension These symptoms indicate increased risk of thrombosis and reduced renal perfusion Life-threatening complications Renal failure Adult respiratory distress syndrome Hemorrhage from ovarian rupture Thromboembolism Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2003;80:1309

4 VEGF and OHSS pathophysiology hcg Granulosa- VEGF Cell membrane VEGF release lutein VEGF cell nucleus Loosen cell junction fluid extravasation mrna VEGF ligand-receptor VEGF receptor-2 Endothelial cell Soares et al. Hum Reprod Update 2008;14:321 Ovarian vessel

Early and late OHSS Early OHSS 1 3 Before pregnancy testing and within 9 days of oocyte retrieval Excessive ovarian response to gonadotropin stimulation and triggering with hcg Rate of preclinical

5 Early and late OHSS Early OHSS 1 3 Before pregnancy testing and within 9 days of oocyte retrieval Excessive ovarian response to gonadotropin stimulation and triggering with hcg Rate of preclinical miscarriage in 1,801 patients undergoing ovarian stimulation for IVF/ICSI 4 p =0.01 Late OHSS 1 3 During early pregnancy ( 10 days after oocyte retrieval) Consequence of endogenous hcg from implanting embryo Associated with lower risk of preclinical miscarriage, compared with early OHSS, but more likely to be severe Dahl Lyons et al. Hum Reprod 1994;9: Mathur et al. Fertil Steril 2000;73: Papanikolaou et al. Hum Reprod 2005;20: Papanikolaou et al. Fertil Steril 2006;85:112

6 Primary risk factors for OHSS Antral follicle counts > 14 High basal AMH levels Previous episodes of OHSS PCOS or isolated PCOS characteristics Young age (< 33 years old) Low body weight Humaidan et al. Steril Fertil 2010 The Practice Committee of the ASRM Fertil Steril 2008; 90:S188.

Every patient needs to be warned about OHSS Every patient undergoing fertility treatment must be informed about OHSS All patients need to be given an emergency number to call if

7 Every patient needs to be warned about OHSS Every patient undergoing fertility treatment must be informed about OHSS All patients need to be given an emergency number to call if any of the following occur: Swelling Pain Breathlessness Nausea Royal College of Nursing. Guidance for fertility nurses Available at Accessed 25/05/10.

8 Treatment of severe OHSS Monitor fluid and electrolyte balance Paracenthesis Prescribe anticoagulation medication to prevent thrombosis and opioids for pain Reduce physical activity Binder et al. Int J Fertil 2007;52:69

9 Preventive strategies for patients at risk of developing OHSS 1. Cycle cancellation before hcg administration (long GnRHa protocol) 2. Coasting (long GnRHa protocol) 3. Cryopreservation of all embryos for future transfer 4. GnRHa trigger (GnRH antagonist protocol) 5. Targeting the VEGF signaling system

10 Cycle cancellation before hcg administration Withholding hcg is the simplest and safest strategy to avoid OHSS in patients at risk Places heavy psychological and financial burdens on the patient After the introduction of coasting, withholding hcg with cycle cancellation is seldom used. Aboulghar. Reprod BioMed Online 2009;19:33.

11 Coasting Withholding gonadotropins, while maintaining GnRH analog administration, until serum estradiol levels drop to a safe level Small and medium follicles enter atresia Larger follicles mature Coasting is widely used, although the scientific evidence for preventing OHSS is not strong Humaidan et al. Fertil Steril 2010; epub.

12 Cryopreservation of all embryos for future transfer Patients undergo oocyte retrieval but not embryo transfer Avoiding fresh-embryo transfer eliminates exposure to endogenous hcg associated with pregnancy and the possibility of late OHSS Does not prevent early OHSS, which is related to the preovulatory exogenous hcg Currently, insufficient evidence to support routine cryopreservation Aboulghar Reprod BioMed Online 2009;19:33.

13 Modifying methods used for triggering final oocyte maturation Triggering dose of hcg can be reduced to IU instead of 10,000 IU 1 Lower doses of hcg did not affect ongoing pregnancy rates in patients with PCOS 2 GnRH agonists can be used to trigger final oocyte maturation in cycles stimulated with: 1 gonadotropins only gonadotropins and GnRH antagonist cotreatment 1. Aboulghar and Mansour. Hum Reprod Update 2003;9: Kolibianakis et al. Fertil Steril 2007;88:1382

14 GnRH agonist triggering in fresh cycles Luteal phase rescued with one bolus of 1500 IU hcg 35 h after triggering 1 3 No significant difference in delivery rate between GnRH agonist triggering plus 1500 IU hcg support and hcg triggering 2 RCT; 302 predicted normal responders Delivery rate: 24% vs. 31%, respectively Pregnancy outcome secured with GnRH agonist triggering followed by 1500 IU hcg support in a pilot study of 12 women at high risk of OHSS 3 1. Humaidan et al. Reprod Biomed Online 2006;13: Humaidan et al. Fertil Steril. 2009;93: Humaidan et al. Reprod Biomed Online 2009;18:630.

15 GnRH agonist triggering successfully avoids OHSS in oocyte donors GnRH agonist triggering has been widely adapted in oocyte donor cycles where the luteal phase can be disregarded Complete elimination of OHSS in donor studies with this method 1,2 Incidence of moderate or severe OHSS in a retrospective study of 2077 cycles (1171 donors) was: 13/1030 cycles (1.26% ) for hcg triggering 0/1046 cycles for GnRH agonist triggering 1 1.Bodri et al. Fertil Steril. 2009;91: Bodri et al. Fertil Steril. 2010;93:2418.

16 VEGF, OHSS and dopamine receptor agonist hcg Granulosa- VEGF Cell membrane VEGF release lutein VEGF cell nucleus Loosen cell junction fluid extravasation mrna VEGF ligand-receptor VEGF receptor-2 Endothelial cell Soares et al. Hum Reprod Update 2008;14:321 Ovarian vessel

17 Dopamine receptor agonist use in high-risk patients Change in endothelial permeability surface area, a measure of vascular permeability Rate of moderate OHSS Placebo Cb2 p = 0.04 p = 0.04 min Baseline hcg 0 hcg + 5 Cabergoline, a dopamine agonist, may be a feasible prophylactic option. Alvarez et al. J Clin Endocrinol Metab 2007;92:2931

18 Summary OHSS is a potentially dangerous complication Early OHSS: due to excessive ovarian response to exogenous gonadotropin + hcg Late OHSS: due to endogenous hcg from implanting embryo Factors predictive of OHSS: PCOS, AFC, AMH, age, BMI number of follicles Preventative strategies: replacing long protocols with GnRH antagonist protocols, GnRHa trigger, total freeze Blocking VEGF signaling

19 Tak for i dag peter.humaidan@midt.rm.dk

Luteal phase rescue after GnRHa triggering Progesterone and Estradiol

Luteal phase rescue after GnRHa triggering Progesterone and Estradiol L. Engmann University of Connecticut Disclaimer Fertility Speaker Bureau Merck Pharmaceuticals Introduction GnRH agonist is effective