IVF Protocols: Hyper & Hypo-Responders, Implantation

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1 IVF Protocols: Hyper & Hypo-Responders, Implantation Midwest Reproductive Symposium June 4-5, Subset : Hyper-Responders Mark R. Bush, MD, FACOG, FACS

OBJECTIVE: Important goals for the PCOS patient undergoing ovarian stimulation for IVF include avoidance of hyperstimulation and the achievement of an ongoing pregnancy.

2 OBJECTIVE: Important goals for the PCOS patient undergoing ovarian stimulation for IVF include avoidance of hyperstimulation and the achievement of an ongoing pregnancy. We sought to examine the efficacy of a once a day, single syringe, mixed preparation of gonadotropins and the potential impact of a selective cut-back regimen. Bush et. al., Fertility and Sterility, Sept 07, S293.

3 MATERIALS AND METHODS: PCOS patients 37 years of age or less in whom there was no prior history of endometriosis or infectious tubal disease were enrolled. All subjects took 1500 mg of extended release metformin daily, 81 mg of aspirin daily, and underwent acupuncture with transfer. Cycles were initiated with birth control pill, luteal GnRH agonist, and a starting dose of IU HP-FSH mixed in the same syringe with 150 IU HP-hMG (which contains 10 IU hcg activity per 75 IU). Depending on physician judgment, either a static dose of gonadotropin was given or it was cut-back. Bush et. al., Fertility and Sterility, Sept 07, S293.

4 For the cut-back, the HP-FSH was first removed. The HP-hMG either remained at the same dose or was also cut-back but never discontinued. In contrast to a protocol utilizing GnRH agonist LH suppression where FSH alone is being cut-back, this approach provided a decreasing dose of FSH while maintaining LH drive to the more mature follicular cohort expressing LH receptors. Bush et. al., Fertility and Sterility, Sept 07, S293.

5 One patient received three day 3 embryos. All other patients received two embryos, 75% of them on day 5. Five patients with hyperstimulation had their oocytes retrieved but did not receive fresh transfer. Two of these patients had the evening GnRH agonist dose replaced with 250 ug of GnRH antagonist during the final 1-2 days of stimulation in an effort to foster more favorable conditions in which to proceed with oocyte retrieval. Bush et. al., Fertility and Sterility, Sept 07, S293.

6 Technique Hyperstimulation Pregnancy Rate (PR)/Cycle PR/embryo transfer (ET) Miscarriage Rate Ongoing PR/ET Patients with cryo Avg# cryo Cut-Back (n=8) 0/8 (0%) 8/8 (100%)* 8/8 (100%) 0/8 (0%) 8/8 (100%) 7/8 (88%) 6 Static Dose (n=14) 5/14 (36%) 8/14 (57%)* 8/9 (89%) 2/8 (25%) 6/9 (67%) 11/14 (79%) 8 *Statistically significant (x 2 ). All other comparisons NS. CONCLUSIONS: A once a day, single syringe, mixed protocol is efficacious for PCOS patients undergoing IVF. As the primary follicular cohort matures, by selectively cutting back FSH dose while maintaining adequate hcg activity, low hyperstimulation rates and excellent ongoing pregnancy rates can be achieved. Bush et. al., Fertility and Sterility, Sept 07, S293.

7 21 oocytes/ 21 PB-1/ ICSI 18 fert, 2 blast ET (9 cryo), viable twins.

8 PCOS Cut Back Protocol Pearls Starting dose 1 vial HP-FSH w/ 2 vials HP-hMG Rarely 2 FSH + 2 FSH/hCG with 1mg dexamethasone PO daily during stim, stay at 0.5mg GnRH agonist Patient seen in AM on d6, reflecting 3 evening doses of med E consider taking away med E take away ½ or 1 vial HP-FSH E2 >1000 take away all FSH and a portion of HP-hMG, but never to 0 vials If cut-back too aggressive, can always add-back 24 hrs later Extrapolate how many days she will need and cut back in anticipation of her predicted rate of rise in E2/follicular response Integration of antagonist salvage tool 5K hcg trigger in most circumstances

10 Antagonist cycle salvage Gustofson,, Larsen, Bush, Segars; ; F&S, Jan 06, pgs OCP lead-in Luteal agonist (0.5 mg/d to 0.25) n = 8 MDF agonist (40 ug/bid) n = 39 If projected E2 >5000 and >25 follicles day of hcg, then antagonist 250/d replaced agonist until day of hcg Gonadotropins maintained at IU/d

Antagonist cycle salvage www.conceptionsrepro.

11 Antagonist cycle salvage Gustofson,, Larsen, Bush, Segars; ; F&S, Jan 06, pgs

12 Antagonist cycle salvage Gustofson,, Larsen, Bush, Segars; ; F&S, Jan 06, pgs E2 levels continue to rise on d1 of coasting Prolonged coasting may impair IVF cycle outcome The incidence of severe OHSS (2.1%) was lower than the published incidence in this high risk group (9-38%) GnRH-I and GnRH-II receptors have been found in granulosa cells, and antagonists may be acting directly on the ovary - particularly considering the reduction in pituitary cell membrane GnRH receptors with the application of GnRH agonist Granulosa cell GnRH receptors may follow later expression pattern as seen with LH receptors Egbase et al, Hum Reprod 2000; 15: Tortoriello et al, F&S 1998; 69: Morris et al, Hum Reprod 1995; 10: Asch et al, Hum Reprod 1991; 6: Khosravi et al, JCEM 2003; 88: Leung et al, Mol Cell Endocrinol 2003; 202: Kang et al, Endocr Relat Cancer 2003: 10:

13 Salazar stim sheet 15 oocytes/ 15 PB-1/ ICSI 14 fert, 2 blast ET (5 cryo), viable twins. 2 yrs prior, LL/rec-FSH only, hyperstim, ET w/o preg, no cryo.

14 Antagonist cycle salvage in hyper-responders responders and as a tool to avoid severe OHSS Replace evening agonist with antagonist Keep gonadotropin dose the same or cut-back Replace antagonist with hcg trigger shot Seven days of antagonist to avoid severe OHSS Patients cancelled prior to retrieval In those patients who go to retrieval but in whom embryos are cryopreserved Donors

15 Cabergoline (Cb2) therapy in face of OHSS VEGF induces VP (vascular permeability) 1,2 Effects of Cb2 attributable to VEGF receptor dephosphorylation 3 Cb2 prevents VP in a dose dependent manner without affecting angiogenesis and implantation in humans (n = 35 treated in face of OHSS) 4 Cb2 reduced the amount of ascites, hemoconcentration and incidence of moderate-severe OHSS 5 Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger 1) McClure, et al, Lancet, 1994; 344: ) Bates, et al, Vascul Pharmacol, 2002; 39: ) Gomez, et al, Endocrinology, 2006; 147: ) Alvarez, et al, Hum Reprod, 2007; 22: ) Alvarez, et al, J Clin Endocrinol Metab, 2007; 92:

16 At 31, peak E2 3707, 10K, 12 2PN, 2 8-cell ET, singleton (2 blast cryo) Now at 36, 24 2PN, 20 biopsy 13/18/21/X/Y, 4 blast XX, 1 blast ET, +7wk

OBJECTIVE: We compared the efficacy of alternative medications for oocyte maturation in IVF cycles in high responders with significant risk factors for ovarian hyperstimulation syndrome (OHSS).

17 OBJECTIVE: We compared the efficacy of alternative medications for oocyte maturation in IVF cycles in high responders with significant risk factors for ovarian hyperstimulation syndrome (OHSS). These medications were leuprolide acetate in conjunction with IU of hcg (dual trigger) or leuprolide acetate alone. DESIGN: Retrospective study of 164 fresh autologous IVF cycles. 119 of which used leuprolide acetate alone and 45 of which used dual triggers. MATERIALS AND METHODS: Patients were stimulated with gonadotropins and pituitary suppression was achieved with ganirelix acetate. For final oocyte maturation, patients were given either 4 mg leuprolide acetate (prior to 2006) or else 4 mg leuprolide acetate plus 1000 to 2500 IU hcg (from 2006). The hcg dose was modulated based on body mass, and was approximately 12 IU per pound of body mass. All patients received luteal phase progesterone and estradiol supplements from retrieval until 8-10 weeks gestation, so that serum levels were maintained above 15ng/ml an d200 pg/ml, respectively. Pregnancy was determined by rising serum titers of hcg 10 days after blastocyst transfer. Ongoing pregnancy was determined by the presence of viable fetal heart motion at 10 weeks gestation. Early pregnancy losses included pregnancies that did not achieve ongoing pregnancy. Wilcoxon s test was used to compare numeric variables and chi-square tests were used to compare categorical variables. Shapiro et. al., Fertility and Sterility, Sept 07, S121.

18 RESULTS: Patients receiving leuprolide alone and those receiving dual triggers did not differ significantly in serum E2 concentration on the day of trigger (mean 5,285 vs. 4,870 pg/ml, respectively), in the number of blastocysts developed (7.2 vs. 5.3) or in the number of embryos transferred (1.8 in both groups), but did have a greater number of mature follicles (30.9 vs. 27.3, P=0.004) and oocytes retrieved (26.0 vs. 20.4, P=0.004). The two groups had similar rates of pregnancy (64.5% per transfer in both groups) but those receiving dual triggers had a lower rate of early pregnancy loss (17.2% vs. 56.3% of pregnancies, respectively, P=0.0004) and a higher ongoing pregnancy rate (53.3% vs. 26.1%, P=0.001). No significant OHSS occurred. CONCLUSIONS: Including 1000 to 2500 IU hcg with leuprolide acetate for oocyte maturation appears to reduce pregnancy loss rates and increase ongoing pregnancy rates when compared to leuprolide acetate alone. This represents lower risk of pregnancy loss than leuprolide acetate alone and may represent lower risk of OHSS than a standard dose of hcg alone. Shapiro et. al., Fertility and Sterility, Sept 07, S121.

19 Extragonadal Functions of the LH/hCG Receptor LH/hCG receptors in multiple uterine cell types, highest levels in endometrial epithelial cells LH/hCG receptor knockout models have abnormal uterine function, including decreased ability to implant donor blastocysts, which cannot be reversed by normalizing E+P levels Uterine Lh/hCG receptor activation upregulates COX-2, increases stromal cell differentiation, modulates pro- and anti-implantation cytokine production, increases blood flow through vasodilation and angiogenesis, inhibits myometrial contractions, and influences resident macrophage populations Filicori et al., F&S, Vol 84, No 2, August 2005,

20 Extragonadal Functions of the LH/hCG Receptor The expression of estrogen and progesterone receptors in the human endometrium has been reported to be altered in ovarian stimulation cycles using GnRH agonists/ antagonists, in which serum LH concentrations in the follicular phase are low (concept of hcg prep) Uterine receptivity is induced by blastocyst hcg signaling superimposed on E/P primed endometrium LH/hCG receptors are upregulated by progesterone in the luteal phase, underscoring the role for this ligand-receptor complex during implantation and placentation Tesarik et al., Repro BioMed Online, Vol 7, No 1, April 2003, Hadi et al., Human Reprod, Vol 9, December 1994, Bourgain et al., F&S, Vol 78, No 2, August 2002, Filicori et al., F&S, Vol 84, No 2, August 2005,

21 hcg affects Uterine Receptivity Independent of Ovarian Function Donor oocytes were split between two sets of recipients, those that ovulated and those that did not (FSH > 30) The ovulating recipients received triptorelin 3.75 mg, and both recipient groups received oral estradiol valerate and vaginally administered micronized progesterone Within each of these groups, half of the recipients received 5000 hcg at the same time as the donor Tesarik et al., Repro BioMed Online, Vol 7, No 1, April 2003, 59-64

22 hcg affects Uterine Receptivity Independent of Ovarian Function Donor Oocytes Recipients: Ovulating 3.75 mg Triptorelin Oral Estradiol and Micronized Vaginal Progesterone Recipients: Non-Ovulating (FSH >30) Received 5000 IU hcg same time as Donor No hcg Received 5000 IU hcg same time As Donor No hcg Tesarik et al., Repro BioMed Online, Vol 7, No 1, April 2003, 59-64

23 hcg affects Uterine Receptivity Independent of Ovarian Function Implantation rate, ovulatory recipients Received hcg: 30.6% Did not receive hcg: 20.7% (P<0.01) Endometrial thickness on transfer day (d19), ovulatory recipients, Received hcg: 9.7mm +/- 0.9 Did not receive hcg: 8.2mm +/- 0.8 (P<0.01), day 14 stagnation was ameliorated There was no difference in the non-ovulatory recipients with tonically elevated LH levels, signifying the effect was mediated through the LH/hCG receptor Tesarik et al., Repro BioMed Online, Vol 7, No 1, April 2003, 59-64

24 Adjunctive hcg in Donor Oocyte Recipients, FET and IVF cycles Donor oocyte recipients and FET cycles receive lupron down-reg, estradiol patches for endometrial proliferation (+ vaginal estradiol as needed), luteal progesterone and estradiol Patients receive 5,000 IU hcg SQ one day before they begin progesterone (for donor recipients this is the same day the donor receives her hcg) Patients then receive 1000 IU days 4, 7 and 10 after the initial dose Fresh IVF cycles utilize 1000 IU days 4, 7 and 10 after the initial hcg dose, with luteal progesterone and estradiol Second serum β-hcg pregnancy test is 8 days after the last 1000 IU injection, allowing for complete clearance (first test greater than 25 c/w pregnancy)

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