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The Evolution of Ovarian Stimulation for ART
“Meet the Expert” - May 2012
Sandro Esteves, MD, PhD Director, ANDROFERT
Center for Male Reproduction Campinas, BRAZIL
1. Historical perspective of gonadotropins development.
2. Primary factors affecting IVF success and ovarian response to stimulation.
3. Taking advantage of new products and clinical strategies to individualize COS.
Esteves, 2
UN Census Estimates, 2008
High-quality oocyte yield
Cycle cancellation, OHSS, multiple
pregnancy
Central Paradigm
Minimize complications
and risks
Maximize beneficial effects
of treatment
Fauser et al., 2008 Esteves, 7
Bassett et al. Reprod Biomed Online 2005;10:169–177; Lunenfeld. Hum Reprod Update 2004;10:453–467. Bosch. Expert Opin. Biol. Ther. 2010;10:1001-1009.
Milestones in the development of gonadotrophins
1949 First hMG extracted
from urine pools
1940 First hCG extracted from human urine
1962 Purified u-hMG
(Pergonal®) and u-hCG (Profasi®)
become available
1980s First FSH-only
product launched (Metrodin®)
1993 First highly purified FSH-only product
launched (Metrodin HP®)
2001 First r-hCG
launched (Ovidrel®/Ovitrelle)
2001 Full recombinant gonadotropin portfolio available
Milestones in the development of r-hFSH 1980
α-subunit sequenced
1983 β-subunit
sequenced
1985 β-FSH gene cloned and expressed in fibroblasts
1988 Human FSH expressed
in Chinese hamster ovary (CHO) cells
1992 First pregnancy
with r-hFSH
2000 First r-hLH launched (Luveris®)
1995 First r-hFSH
launched (GONAL-f®)
2002 First filled-by-mass
product launched (GONAL-f® FbM)
2008 First
r-hLH+r-FSH combined
(Pergoveris®)
Esteves, 8
1. Demand increased
From urinary to recombinant
2. Safety - Impurities in Urinary-derived Drugs
FSH Protein
impurities
hMG HP 30% of impurities per
vial with (different proteins identified) varying
from batch to batch
van de Weijer et al. Reprod Biomed Online 2003;7:547–557 Kuwabara Y et al, J Reprod Med 2009; 54:459–466
Impossibility to trace donor source
Quality cannot be checked during transportation
Decontamination may denature proteins
Cross‐contamination cannot be avoided
Many of the protein contaminants are active and have unknown
effects
Suboptimal testing for consistency and purity
Cell attachment and proliferation
r-hFSH production and secretion
Collection of cell culture supernatant medium containing r-hFSH
In-process QC
Esteves, 11
Concentration of
supernatant
Chromatographic purification steps
Ultrasterile filtration
Characterization and full QC of bulk r-hFSH
Culture media Harvest Bioreactor
u-hMG HP (5 batches) r-hFSH
(follitropin alfa)
Merck Serono data on file
Molecular weight
markers Esteves, 12
2. Safety - Impurities in Urinary-derived Drugs
Impurities cannot be associated
with a better or worse outcome
but certainly are not needed
for COH
Typical Cycle (long
protocol): Daily SC GnRH-a: x21
HMG/FSH: x10-15
hCG: x1
Progesterone: x14
Blood tests: x4-7
Number of sticks: 36-57
Bassett et al. Reprod Biomed Online 2005;10:169–177.
Purity (FSH
content)
Mean specific FSH activity
(IU/mg protein)
Injected 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 6.1
Esteves, 14
1. Bassett et al. Reprod Biomed Online 2005;10:169–177; 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46.
Conventional Bioassay
High
variability
Rat ovary weight gain
FbM: Novel analitycal method
Protein content by mass
Minimal batch-to-batch variability (1.6%)1,2
Urinary gonadotropins Follitropin beta Follitropin alfa
Esteves, 15
Esteves, 16
1930s 1950 1980 1995 2003
Horse PMSG
Pituitary FSH u-hMG
u-FSH
u-FSH HP r-hFSH
r-hFSH FbM
Intramuscular administration sc Injector pens
sc, subcutaneous; FbM, filled by Mass; HP, highly-purified
Safety, Quality, Consistency and Patient
Convenience
For clinicians: Manufactured to the highest standards of quality and consistency;
Delivers a guaranteed dose.
For patients: Best convenience; Improve satisfaction & treatment compliance.
Advantages of Novel Products
Esteves, 18
2. Primary factors affecting IVF success and ovarian response to stimulation.
Esteves, 19
Esteves, 20
Negative Predictors
Positive Predictor
van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589.
Female Age Duration of infertility Basal FSH Type of infertility Indication Fertilization method Number of oocytes retrieved Number of embryos transferred Embryo quality
All reflecting ovarian reserve
Ovarian Response to Gonadotropin Stimulation
Demographics and anthropometrics (Age, BMI, Race)
Genetics profile Cause of Infertility Years of Infertility Health status Nutritional status
Akande et al. Hum Reprod 2002;17:2003–2008.
(n = 1019)
20–24 25–29 30–34 35–39 40–44 45–49
5
0
10
15
20 Li
ve b
irths
(%)
Age (years)
6–8.9
3–5.9
<3
FSH IU/L
≥12
9–11.9
Chronological vs Biological Ageing
Esteves, 22
La Marca et al. Hum Reprod 2009.
= remaining population of primordial and resting follicles
Esteves, 23
Anti-Mullerian Hormone levels are
correlated with the
number of follicles at
gonadotropin independent
stage.
Antral Follicle Count (AFC)
Devroey et al. Hum Reprod Update 2009; Broekmans et al. Fertil Steril 2009.
Hansen KR, et al. Fertil Steril 2003;80:577–83
Number of antral follicles
Mea
n nu
mbe
r of o
ocyt
es re
treiv
ed
r=0.64 p<0.001
0 5 10 15 20 25
25
20
15
10
5
0
Esteves, 24
Number of antral follicles present in the ovaries at a given time that can be stimulated into dominant follicle growth by exogenous
gonadotropins.
AMH = AFC >Inhibin B >FSH >Age
Esteves, 25
Excessive Response Predictor Poor Response Predictor
Broer et al. Fertil Steril, 2009; Broer et al. Hum Reprod Update 2011.
*Bologna criteria: Ferraretti et al. Hum Reprod 2011; Broer et al. Hum Reprod Update 2011; Nelson et al. Hum Reprod. 2009;
Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007.
AMH and AFC – Operational Purposes
Esteves, 26
Response to Ovarian
Stimulation
Anti-Mullerian Hormone (ng/mL)
Antral Follicle Count
False Positive
Rate
Risk of Excessive Response (≥15 oocytes or OHSS)
≥ 3.5
> 15
~15% Risk of Poor Response (≤ 4 oocytes)*
< 1.1
< 5
Esteves, 27
Tailoring gonadotropin dose using recombinant FSH fbM pre-filled ready-to-use pen devices.
Exploring the flexibility of GnRH antagonist protocols.
Improving success in IVF by identifying the subgroups of patients who benefit from LH supplementation.
Unselected group of NG down-regulated women (n=865) Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236)
Gonadotropin rFSH/hMG 112.5-450 UI Individualized dose
Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed)
Day 1
Day 6
Day of hCG
Cycle day 21
Day 2-5 of menses
menses
Vaginal progesterone
Esteves, 28
Reproductive Biology and Endocrinology 2009; 7:111.
Outcome Measure HMG n=299
HP-hMG N=330
r-hFSH n=236
P-value
Total gonadotropin dose (IU) 2,685 2,903 2,268 <0.01 Retrieved oocytes (N) 10.9 10.7 10.8 NS MII oocytes (N) 8.9 8.9 8.7 NS 2PN fertilization rate (%) 72 72 71 NS Implantation rate (%) 24 27 23 NS
Live birth rate per cycle (%) 24.4 32.4 30.1 NS Moderate/severe OHSS(%) 2.3 1.8 1.3 NS
Esteves et al, Reprod Biol Endocrinol. 2009; 7:111
To achieve a live birth,
21-52% more HP-hMG and
hMG was required
compared with r-hFSH
Tota
l Dos
e per
Live
Birt
h (IU
)*
0
3,000
7,000
10,000
21.6%
r-hFSH HP-hMG
6,324*
7,739
hMG
9,690 52.2%
* Mean total dose per cycle/Live birth rate (≤35 years)
18.7 20.3
53.4* % Cycles with “Step-down” during ovarian stimulation
HMG HP-HMG rec-hFSH (fbm)
*P<0.01
Evidence-based truth: Rec-hFSH is more
potent ↑ 3.1 oocytes (Bosch, 2008)
↑ 1.8 oocytes (MERIT, 2006)
↑ 2.8 oocytes (Hompes, 2007)
Scientific truth: Rec-hFSH is
purer
Non urine-extracted product
Recombinant technology
Esteves, 32
Batch variability +20%, -25%
225
270
170
IU
Bioassay Urinary and Follitropin beta
16.5 mcg (225 IU)
Filled by Mass Folitropin alfa (Gonal-f)
Batch variability ± 2%
Risk of OHSS
Poor response
62% • Incidence of
Infertility (WHO II)
67% • Infertile Patients with PCOS
(WHO II)
41% • Prevalence of Patients with PCOS
in Clinical Practice
Treatment Management of Infertility GCC Countries (IPSOS May 2008) Yeko et al. Fertil Steril 2004; Keck et al. RBM Online 2005.
31.3% 31.1% 35.3%
50.0%
20.0%
0%
10%
20%
30%
40%
50%
60%
75 IU 112.5 IU 150 IU 187.5 IU 225 IU
Clinical pregnancy rates/cycle started
Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:95–204.
Individualized dosing in increments of 37.5 IU of Folitropin alfa possible by FbM technology
Use of algorithm of patients characteristics
● basal FSH ● body mass index (BMI) ● age ● antral follicle count
Age (28-32)
Oocytes retrieved (8-12)
Esteves, 35
CONSORT = CONsistency in r-hFSH Starting dOses for Individualized tReatmenT: ART results
Esteves, 36
1. Rec-hFSH fbM is purer, safer and more potent than urinary gonadotropins.
2. Lower starting doses and step-up/step-down (by 37.5 UI) COS is advisable.
Exploring the flexibility of GnRH antagonist protocols.
Esteves, 37
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
Activation of the GnRH receptor
Regulation of receptor affinity
Regulation of receptor biological activity
Antagonistic effect
1 3 2
Agonist administration
Gonadotropin administration Long GnRH
agonist protocol
Antagonist administration
Gonadotropin administration
GnRH antagonist protocol
Longer treatment
Can exclude early
pregnancy
Can be integrated in spontaneous and OI cycles
Pre-treatment cycle Treatment cycle
Flare up effect
Pituitary suppression
No hormonal withdrawal
No flare effect with
possible cyst formation
Shorter duration of stimulation
Prevent OHSS by GnRH-a
Esteves, 40
N studies 45 22
Included IUI cycles
Yes No
N patients 7511 3176
Primary outcome OPR or LBR LBR
Odds-ratio 0.86 (95% CI: 0.69-1.08)
0.86 (95% CI: 0.72-1.02)
1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750. 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Probability of Live Birth
Esteves, 41
Duration of OS -1.13 days (-1.83; -0.44)
-1.54 days (-2.42; -0.66; p=.0006)
Oocytes retrieved -- -1.19 (-1.82; -0.56)
Risk of severe OHSS
0.43* (95% CI 0.33-0.57)
0.61 (0.42; 0.89; p=.01)
1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750. 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
Duration of OS and Risk of OHSS
Esteves, 42
POOR RESPONDERS 14 RCT (1127 patients); Pu et al. 2011
Duration of stimulation
Oocytes retrieved
Cycle cancellation
CPR
-1.9 days (-3.6; -0.12)
-0.17 (-2.42; -0.66)
1.01 (0.71; 1.42)
1.23 (0.92, 1.66)
Lainas et al. Hum Reprod. 2010;25:683; Pu D et al. Hum Reprod. 2011; 26: 2742.
PCOS RCT; 220 patients; Lainas et al. 2010
Days of stimulation
Oocytes retrieved; N
Grades II + III OHSS (%)
CPR (%)
10 vs 12 (P<.001)
27 vs 28 (P=0.22)
44 vs 65 (P=0.006)
50.9 vs 47.3 (P=0.68)
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%*
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.
*P < 0.01
Individualized Treatment with AMH AMH + antagonists in hyper-responders
Esteves, 43
GnRH-a triggering (0.2-1.5 mg): antagonist protocol; Reduced if not eliminated risk for OHSS;
In specific high risk patients for OHSS and egg donation programs should become the choice
Challenge is to rescue luteal phase insufficiency; Modified luteal support improved delivery rate:
hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined
Delivery rates: 18% risk difference favoring hCG (before) X 6% risk (after modified luteal support)
Esteves, 44 Humaidan et al. Hum Reprod Update 2011.
Esteves, 45
1. GnRH antagonists improve COS flexibility.
2. Duration of stimulation is decreased by 1-2 days (gonadotropin total dose by 10-20%).
3. Use of GnRH antagonists in COS reduces (or eliminate) the risk of severe OHSS.
Esteves, 46
1st Level: Antagonist rather than Agonists. 2nd Level: In patients on antagonist protocol at risk of OHSS, replace hCG with GnRH-a for oocyte maturation trigger. 3rd Level: In patients with early OHSS onset, use of GnRH-ant luteal phase.
OHSS: Three Levels of Protection
Esteves, 47
19992009
15%
60% Cycles with GnRH
Antagonists
9%
39%
52%
r-hFSHr-hFSH+hMGhMG
Data supplied by REDLARA and ICMART
2009
Esteves, 48
Esteves, 49
• Mild Stimulation (low dose rec-hFSH + GnRH ant.):
• 5 oocytes retrieved;
• IR = 31%
• Conventional Stimulation :
• 10 oocytes retrieved;
• IR = 29%
Verberg et al. Hum Reprod Update 2009; 15: 5–12.
Promotion of Steroidogenesis (TCs) early FP
• Adequate estrogen production • Uterine/endometrial
changes
Stimulation of final Follicular Maturation (GCs) late FP
Esteves, 49 Alviggi et al. Reprod Biomed Online 2006;12:221.
Esteves, 50
• Mild Stimulation (low dose rec-hFSH + GnRH ant.):
• 5 oocytes retrieved;
• IR = 31%
• Conventional Stimulation :
• 10 oocytes retrieved;
• IR = 29%
Verberg et al. Hum Reprod Update 2009; 15: 5–12. Esteves, 50 Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.
THRESHOLD
CEILING
• Suppression of GC proliferation • Follicular atresia (non-dominant follicles) • Premature luteinization • Oocyte development compromised H
igh
• Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation
Nor
mal
• Insufficient androgen (and estrogen) synthesis • Follicular growth and maturation impaired • Inadequate endometrial proliferation Lo
w
Esteves, 51
• Mild Stimulation (low dose rec-hFSH + GnRH ant.):
• 5 oocytes retrieved;
• IR = 31%
• Conventional Stimulation :
• 10 oocytes retrieved;
• IR = 29%
Verberg et al. Hum Reprod Update 2009; 15: 5–12. Esteves, 51
• ~80% normogonadotropic women undergoing ART1-3
Nor
mal
• 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)4
• Poor responders5
• Slow/Hypo-responders6
• Deeply suppressed endogenous LH (endometriosis)7
Low
1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod 2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175
5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al. RBMOnline 2009. 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637;
7
Esteves, 52
Women with Less Sensitive Ovaries Poor Responders*
At least 2 of the following: Advanced maternal age (≥40 years) Previous POR (≤3 oocytes with a conventional stimulation protocol) Abnormal ovarian reserve test (AFC<5; AMH <1.1) Or: 2 episodes of POR after maximal stimulation
Hypo/Slow Responders Normal markers of ovarian reserve; Hypo-responders: d1-d7: normal initial follicullar recruitment using fixed starting dose of FSH; d7- d10: plateau on follicullar growth despite continuing same FSH dosage Slow responders: High doses of FSH (>3,000UI) to promote follicular growth; May indicate genetic polymorphisms of LH and/or FSH receptor
*Bologna criteria: Ferraretti et al. Hum Reprod 2011; Alviggi, et al. RBM Online 2009; De Placido et al. Hum Reprod. 2004; 20: 390-6;
Ferraretti et al. Fertil Steril. 2004; 82: 1521-6.
Increasing FSH drive of limited value
LH
LH
FSH
• Theca cells
• Granulosa
cells
Consider increasing LH drive
There is a potential role for r-hLH in women with less sensitive ovaries
Esteves, 53
Hill MJ et al. Fertil Steril 2012; 97: 1108-4.
Comparison of Clinical Pregnancy Rates
Rec-hLH for older women (≥35 years)
Esteves, 54
Rec-hLH for Poor Responders
Cochrane review 2007: Poor-responders using r-hFSH vs r-hLH + r-hFSH (Ongoing PR) Esteves, 55
Esteves, 56
Deeply Suppressed Endogenous LH
6 9 11 10 14
18 22
32 40
FSH step-up (+150 UI) LH supplementation(+150 UI)
Normal Responders
Mean No. oocytes retrieved IR (%) OPR (%)
De Placido et al. Hum Reprod. 2004; 20: 390-6.
RCT 260 pts; “Steady” response on D8 (E2 <180pg/mL; >6 follicles <10mm)
Esteves, 57
8 11 11 14
37 35
22
41 37
rec-hFSH step-up rec-hLHsupplementation
Control
Mean No. oocytes retrieved IR (%) LBR (%)
Ferraretti et al. Fertil Steril. 2004; 82: 1521-6.
RCT 180 pts; follicular stagnation d7-d10 LH for Slow/Hypo Responders
Esteves, 58
1. LH supplementation to COS increase IVF success in patients subgroups: i. Advanced female age (≥35 years) ii. Poor responders iii. Slow/Hypo-responders iv. Profound LH suppression after down-
regulation (endometriosis pts.) 2. 75-150 UI/day is sufficient. 3. Take advantage of rec-hLH fbM.
The Evolution of Ovarian Stimulation for ART
1. Using markers of ovarian reserve (AMH; AFC) 2. Using better drugs (rec-gonadotropins FbM) 3. Mild stimulation (PCOS) 4. Flexibility of antagonist protocols 5. LH supplementation 6. Integrate strategies to maximize beneficial
effects of treatment and minimize risks and complications.
Esteves, 59
Psychological burden 49%-26%
Prognosis 40%-23% Cost of treatment 23%-0% Relationship/divorce 15%-9% Physical burden 7-6%
Up to 65% of couples dropout from IVF without achieving pregnancy
before they complete 3 cycles
Oocyte retrieval 52%
Embryo transfer 29%
Injections 29%
Physical pain 20%
Blood tests 14%
1. Olivius K t al, Fertil Steril 2004;81:258; 2. Land JA et al, Fertil Steril 1997; 68:278; 3. Schroder AK, et al, RBM Online 2004; 5:600; 4. Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; 5. Rajkhowa M et al, Hum Reprod 2006; 21:358; 6. Brandes M et al, Hum Reprod 2009;
24:3127; 7. Hammarberg K et al, Hum Reprod 2001; 16:374.
Reasons
Color-coded for differentiation
The New Family of PensTM:
• same injection device design for all gonadotropins;
• first & only pre-filled, ready-to-use family of pens for fertility treatment.
Esteves, 61
Consider a change...
Esteves, 62
