Strategies to improve ovarian stimulation

MerckSerono Stand-alone Meeting Cochin, India – August 2011Strategies to Improve Success in Ovarian Stimulation

Learning Objectives

UN Census Estimates, 2008

Ovulation Inductionfor ARTPharmaceutical industryOne size fits all protocol for OS suppress LH surge: GnRHa ovarian stimulation with HMG/FSH high doses of gonadotropin high number oocytes high number of embryosResults not the same for all poor response and OHSS side effects patient satisfaction neglected

Ovulation InductionOne size fits all? Patient is the mainvariable of OI response  Demographics and anthropometrics (Age, BMI, Race)  Genetics profile  Cause of Infertility  Years of Infertility  Health status  Nutritional status

What we really want to know in OI is... How to define the right individual treatment for the right patient to: ●Prevent poor response and OHSS (reduce cancellation) ●Reduce side effects ●Increase pregnancy rates ●Reduce physical, psychological and financial burdenEsteves, 9

Understanding the Problem From cookery to science Individualizing ovarian stimulation according to patients is important But how ? There are several predictors of ovarian response Can we make prediction more scientific but simple ?Esteves, 10

Learning Objectives Gonadotropins: better now

Markers of Ovarian Response Can we predict ovarian response? Age Biomarkers ● Hormonal Biomarkers, FSH, Inhibin-B, AMH ● Functional Biomarkers: Antral Follicle Count (AFC) ● Genetic Biomarkers: Single Nucleotide Polymorphisms for FSH-R/LH/LH-R/E2-R/AMH-REsteves, 12

Who has the highest chance of a live birth following IVF? Hana Maria Age 26 Age 37 Basal FSH 9 Basal FSH 5Esteves, 13

Age and FSH chronological vs biological in IVF 20 FSH IU/L Hana Maria <3 15 Live births (%) 3–5.9 6–8.9 10 9–11.9 5 ≥12 (n = 1019) 0 20–24 25–29 30–34 35–39 40–44 45–49 Age (years)Esteves, 14 1. Akande et al. Hum Reprod 2002;17:2003–2008

Why do ovaries age at different rates? Multifactorial, but genetics important FSH-R: Ser680 genotype Single nucleotide polymorphisms Human FSH Receptor Mutations (SNPs) linked to: - NH2 ● Ovarian response to gonadotrophins Ile160Thr Ala189Val (Asn191Ile) ● Premature menopause Asp224Val * Pro346Arg Thr307Ala Val341Ala Pro519Thr * Both activating and inactivating Leu 601Val mutations identified in the LH and Arg573Cys FSH receptor genes1 Ala419Thr Asp567Gly?? * - COOH * Ser680AsnEsteves, 15 1. Themmen and Huhtaniemi. Endocr Rev 2000;21:551–583

Markers of Ovarian Response Biomarkers and follicular development AMH levels are correlated with the number of follicles at gonadotropin independent stage La Marca, et al. Hum Reprod 2009.Esteves, 16

Markers of Ovarian Response anti-Mullerian hormone (AMH) Retrospective analysis, 316 patients (1st IVF cycle) in GnRH-a long protocol Variables: age, basal FSH, AMH, Inhibin-B Endpoint: number of oocytes Cut-off of poor response: 4 oocytes AMH: a cut-off 1.26 ng/ml was able to predict poor response (<4 oocytes) with 97% sensitivityEsteves, 17 Gnoth, et al. Hum Reprod 2008.

Markers of Ovarian Response Prediction of response by AMH AMH category 0.14 to <0.7 0.7 to <2.1 >2.1 (ng/mL) (N=74) (N=128) (N=148) Agonist protocol + 375 225 150 rFSH Oocytes (n) 5 (3-7) 10 (7-15) 14 (10-19) Severe OHSS 0 (0%) 3 (2%) 20 (13.9%) Cancellation 19 (25.7%) 3 (2.3%) 4 (2.7%) CPR per transfer 11.1% 34.6% 40.1% Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009 ;24(4):867-75.Esteves, 18 Verhagenet al. 2008; Broer et al., 2010

Markers of Ovarian Response Antral Follicle Count (AFC) No. of antral Mean number of oocytes retreived 25 <3 4-10 > 10 follicles 20 No. of cycles 16 76 57 Mean age 15 36.8 36.3 32.8 (years) r=0.64 10 p<0.001 Day 3 FSH 12.7 7.1 5.6 (IU/l) 5 Cx rate 68.8% 5.3% 0% 0 Peak E2 432 1,001 1,912 0 5 10 15 20 25 (pg/ml) Mean No. of Number of antral follicles 2.0 ± 0.9 6.3 ± 4.4 14.1 ± 8.5 eggs Hansen KR, et al. Fertil Steril Pregnancy 0% 13.2% 26.3% 2003;80:577–83 rateEsteves, 19 Chang, et al. Fertil Steril. 1998;69:505.

Markers of Ovarian Response Prediction of response AMH = AFC >Inhibin B >FSH >AgeEsteves, 20 Broer et al. , 2010

Markers of Ovarian Response Summary The patient individual factors play a crucial role in predicting ovarian response. AFC and AMH are helpful to predict ovarian response to stimulation.Esteves, 21

Learning Objectives

Gonadotropins:  Recombinant FSH/LH/hCG  Urinary FSH/LH/hCG GnRH Analogues:  Agonist Other:  Antagonist  Progesterone  Estradiol  Aromatase inibitor  Contraceptive pill  Antioxidants/vitaminsEsteves, 23

Gonadotropins: an overviewWhat is available? Product Technology Brand name ManufacturerhMG Urine-derived Menogon®; Repronex® Ferring Merional® IBSAhMG HP Urine-derived Menopur® Ferringu-FSH Urine-derived Fostimon® IBSAu-FSH HP Urine-derived Bravelle® Ferringu-hCG Urine-derived Choragon® Ferring Choriomon® IBSAr-hFSH (follitropin Recombinant Puregon®; Follistim® MSDbeta)r-hFSH (follitropin alfa) Recombinant GONAL-f® MerckSeronor-hLH Recombinant Luveris® MerckSeronor-FSH + r-hLH Recombinant Pergoveris® MerckSeronor-hCG Recombinant Ovidrel®; Ovitrelle® MerckSerono

Gonadotropins: an overviewUrinary-derived products

Gonadotropins: an overview Recombinants Bioreactor Harvest Culture media Production Purification Cell attachment and Concentration of proliferation supernatant r-hFSH production and Chromatographic secretion purification steps Collection of cell culture supernatant Ultrasterile filtration medium containing Characterization r-hFSH and full QC of In-process QC bulk r-hFSHEsteves, 26

Gonadotropins: an overview Differences Purity Mean specific Injected (FSH FSH activity protein content) (IU/mg protein) per 75 IU (mcg) hMG < 5% ~100 ~750* hMG-HP < 70% 2000–2500 ~33* r-hFSH Follitropin beta – 7000–10,000 8.1* Follitropin alfa > 99% 13,645 6.1Esteves, 27 Bassett et al. Reprod Biomed Online 2005;10:169–177

Gonadotropins: an overview Product Quality: Filled by Mass (FbM) Novel analitycal Conventional method Bioassay Physiochemical technique High in vivo (rat) variability Minimal batch-to- (~20%) batch variability (1.6%)1,2 1. Bassett et al. Reprod Biomed Online 2005;10:169–177 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46Esteves, 28

Concept of Dose PrecisionClinical implications Batch variability Batch variability +20%, -25%  2%IU Risk of OHSS270 16.5 mcg225 (225 IU)170 Poor response Bioassay Filled by Mass Urinary and Follitropin beta Folitropin alfa (Gonal-f FbM)

Portable, ready-to-use device Precise dose delivered Gonal-f FbM

Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236) Day Day 1 Day 6 of hCG Cycle day 21 Gonadotropin rFSH/hMG Individualized dose 112.5-450 UI Vaginal progesterone Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed) mensesEsteves, 31 Day 2-5 of menses

r-hFSH vs hMG/HP-hMG in ART Esteves et al. (observational study 2009)Outcome Measure HMG HP-hMG r-hFSH P- n=299 N=330 n=236 valueTotal gonadotropin dose (IU) 2,685 2,903 2,268 <0.01Retrieved oocytes (N) 10.9 10.7 10.8 NSMII oocytes (N) 8.9 8.9 8.7 NS2PN fertilization rate (%) 72 72 71 NSImplantation rate (%) 24 27 23 NSLive birth rate per cycle (%) 24.4 32.4 30.1 NSModerate/severe OHSS(%) 2.3 1.8 1.3 NS Esteves et al, Reprod Biol Endocrinol. 2009; 7:111

r-hFSH vs hMG and HP-hMG in ARTEsteves et al. (observational study 2009) % Cycles with “Step-down” during ovarian stimulation 53.4* *P<0.01 18.7 20.3 HMG HP-HMG rec-hFSH (fbm) Esteves et al, Reprod Biol Endocrinol. 2009; 7:111

r-hFSH vs hMG and HP-hMG in ART Esteves et al. (observational study 2009)Total Dose per Live Birth (IU)* To achieve a 10.000 live birth, 52.2% 9,690 21-52% more 7.000 21.6% 7,739 HP-hMG and 6,324* 3.000 hMG was required 0 compared r-hFSH HP-hMG hMG with r-hFSH * Mean total dose per cycle/Live birth rate (≤35 years) Esteves et al, Reprod Biol Endocrinol. 2009; 7:111

Other products for ART What is available? Product Brand name ManufacturerGnRH-analogueNafareline Synarel® PfizerLeuprolide Lupron® AbbottTriptoreline Decapeptyl® FerringGosereline Zoladex® Astra-ZenecaBusereline Suprefact®, Suprecur® Sanofi-AventisGnRH antagonistCetrorelix Cetrotide® Merck SeronoGanirelix Orgalutran® MSDProgesterone8% gel Crinone® Merck Serono100 capsules Utrogestan® FerringOil solution 50mg Several Several

LH surge preventionGnRH agonists pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Regulation of Regulation of receptor GnRH receptor receptor affinity biological activity

LH surge preventionGnRH antagonists 1 2 3pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the Antagonistic Regulation of Regulation of receptor GnRH receptor effect receptor affinity biological activity

LH surge prevention GnRH antagonists Agonist FollicularLH, FSH 30 E2 , P 4 Luteal 20 2-4 weeks 10 Synchronized follicles 0 6 • Half-life ~20h (Cetrorelix) Antagonist 5 • Suppress LH by 80% of 4 baseline levels LH (IU/L) 3 Antagonist 2 1 0 -6 0 6 12 18 24 30 36 42 48 Hours

A comparison of Nafarelin and Cetrorelix for LH suppression in COH-ICSI cycles with Follitropin alfa • Retrospective (2002-2008) • Unselected group of NG women – COS with r-hFSH • Group 1 (Nafarelin; N=1,362); Group 2 (Cetrorelix; N=414) Day 1 Follicle Day of rFSH 13 mm of hCG Follitropin alfa dose Individualized 112.5-450 UI rFSH dose Vaginal menses 0.25 mg/day of progesterone Day 2 or 3 Cetrorelix (flexible) of menses Day 6 Day Day 1 of hCG of rFSH of rFSH Cycle Gonadotropin dose day 21 Individualized dose 112.5-450 UI Vaginal progesterone Agonist: Nafarelin acetate (400 mcg/day; fixed) menses Day 2-5 of mensesEsteves, 39 Esteves et al., JBRA Assist Reprod (Suppl 1), 2010

A comparison of Nafarelin and Cetrorelix for LH suppression in COH-ICSI cycles with Follitropin alfa Distribution by ICSI cycle rank (%)1st ICSI cycles Cetrorelix Nafarelin P-value N=163 N=948 Nafarelin CetrorelixAge (yrs) 34.5 33.4 0.002 15Total r-hFSH dose (IU) 2,313 2,453 0.001 36 46 50Days of -hrFSH 9.9 10.3 0.01E2 hCG day (pmol/L) 1,585 2,371 <0.001Oocytes retrieved (n) 9.5 11.3 <0.001 85 642PN Fertilization (%) 63.3 62.5 NS 54 50Transfer (n) 2.4 2.5 NSLive birth (%) 35.5 36.3 NS cycle no.1 cycle no.2 cycle no.3 cycle no.Embryo cryopreserved (%) 47.1 48.4 NS (n=1111) (n=378) (n=194) ≥4 (n=93) Esteves et al., JBRA Assist Reprod (Suppl 1), 2010

GnRH antagonists vs agonists Meta-analysis Kolibianakis et al (2006)2 N studies 22 Included non peer-reviewed data No Included IUI cycles No N patients 3176 Odds ratio 0.86 (0.72-1.02; p=.08)* Duration of stimulation -1.54 days (OR: -2.42; -0.66; p=.0006) Oocytes retrieved -1.19 (OR: -1.82; -0.56) Risk of severe OHSS OR=0.61 (0.42; 0.89; p=.01)* *For every 59 women treated with a GnRH agonist vs GnRH antagonist, one additional case of severe OHSS will occur.Esteves, 41

LH surge prevention GnRH antagonists vs agonists Prevent OHSS Can be integrated by GnRH-a No flare in spontaneous Single or multiple effect with No hormonal and OI cycles Antagonist dose GnRH administration possible cyst withdrawalantagonist protocol formation Gonadotropin administration Less gona- Can exclude dotropins early pregnancy Flare up Pituitary effect suppression Gonadotropin administration Long GnRH agonist protocol Longer Agonist administration treatment Pre-treatment cycle Treatment cycle

Learning Objectives

Individualized Treatment with AMH AMH + antagonists in hyper-responders AMH category (ng/mL) >2.1 GnRH analogue + r-hFSH 150UI Agonist Antagonist Oocytes (n) 14 (10-19) 10 (8.5-13.5) Severe OHSS 20 (13.9%) 0 (0%)* Cancellation 4 (2.7%) 1 (2.9%) CPR per transfer 40.1% 63.6%* *P<0.01 Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009 ;24(4):867-75.Esteves, 44

CONSORT = CONsistency in r-hFSH Starting dOses for Individualized tReatmenT Individualized dosing in Clinical pregnancy rates/cycle increments of 37.5 IU of started 60% Gonal-f possible by FbM technology 50% 50.0% 40% Use of algorithm of 30% 35.3% patients characteristics 31.3% 31.1% ● basal FSH 20% ● body mass index (BMI) 20.0% ● age 10% ● antral follicle count 0% 75 IU 112.5 IU 150 IU 187.5 IU 225 IU Age (28-32) Oocytes retrieved (8-12) Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:195–204.Esteves, 45

LH supplementation in ART What do we know today  The majority of patients do not need LH supplementation as endogenous LH levels are sufficient1–3  15-20% of women have less sensitive ovaries Older patients (> 35 years)4 Low responders5 Deeply suppressed endogenous LH6 Hypo-responders7 FSH and AFC considered adequate Genetic characteristics Single nucleotide polymorphisms of FSH-R and LH-R 1. Alviggi et al. Reprod Biomed Online 2006;12:221–233; 2. Tarlatzis et al. Hum Reprod 2006;21:90–94 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175–182 5. Mochtar MH, Cochrane Database, 2007; 6. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637–643 7. Alviggi, et al. RBMOnline 2009.Esteves, 46

LH supplementation in ARTCochrane review 2007: hypo-respondersr-hFSH vs r-hLH + r-hFSH (Ongoing PR) No difference in basal LH levels. Less bioactive LH/LH receptor polymorphism ? Mochtar MH, Cochrane Database, 2007

LH supplementation in ART Biologic older (less sensitive) ovaries LH • Theca cells Consider increasing LH drive LH • Granulosa cells Increasing FSH drive of limited FSH value There is a potential role for r-hLH in this populationEsteves, 48

Tailoring Ovarian StimulationTreatment individualization strategies High • Antagonist + r-FSH FbM 112.5-150 UI Responders • Normal oocyte yield AFC >10 • Very low cancellation/OHSS • Adequate LBR AMH >2.1 Normal • Antagonist or Agonist + r-hFSH 187.5-262.5 UI Responders • Low cancellation & OHSS AFC 4-10 • Adequate LBR AMH 0.7-2.1 Poor • Antagonist + r-hFSH (+r-hLH) 300-375 UI Responders • Short stimulation AFC <4 Moderate cancellation AMH <0.7 Low LBR

From cookery to science – Practical Points We can we make prediction more scientific but simple AMH and AFC We can tailor OS according to patients characteristics Using markers Using better drugs (FbM) Dose reduction (PCOS) Antagonist protocol GnRHa LH triggering LH supplementationEsteves, 50

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Strategies to improve ovarian stimulation

by Sandro Esteves on Aug 10, 2011

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