1. Jordan, Lebanon, Kuwait, Qatar, Bahrain – Nov 2012
Individualization of Patient
Treatment
Sandro Esteves, M.D., Ph.D.
Director, ANDROFERT
Center for Male Reproduction & Infertility
Campinas, BRAZIL

2. What is in it for me?
Use of Biomarkers to Individualize Ovarian
Stimulation Protocols
Recent Advances in Injectable Gonadotropins
Preparations
 Rec-FSH vs Urinary Products
 Agonist versus Antagonist GnRH
 To whom to give rec-hLH? Differences between
rec-hLH and LH Activity in HMG Preparations?
Strategies to Improve Ovarian Stimulation
 Best Protocols to Minimize Risks and Reduce
Dropout Rates in IVF and IUI/OI
Esteves, 2

3. Level of
evidence
Individualization of Patient Treatment
Lecture Structure
 Points I Consider Highly Relevant in Clinical Practice;
 Arguments Supported by Studies with High Level of Evidence.
Level Type of evidence
1a Obtained from meta-analysis of randomised trials
1b Obtained from at least one randomised trial
2a Obtained from one well-designed controlled study without
randomisation
2b Obtained from at least one other type of well-designed quasi-
experimental study
3 Obtained from well-designed non-experimental studies
(comparative and correlation studies, case series)
4 Obtained from expert committee reports or opinions or clinical
experience of respected authorities
Esteves, 3 Modified from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009)

4. Individualization of Patient
Treatment
Esteves, SC – Nov 2012
Review this Lecture at:
http://www.androfert.com.br/review
Esteves, 4

5. What is in it for me?
Use of Biomarkers to Individualize Ovarian
Stimulation Protocols
Recent Advances in Gonadotropins Preparations
 Rec-FSH vs urinary products
 GnRH Agonist versus Antagonist
 To whom to give rec-hLH? Differences between rec-
hLH and LH activity in HMG preparations?
Strategies to Improve Ovarian Stimulation
 Best Protocols to Minimize Risks and Reduce Dropout
Rates in IVF
Esteves, 5

6. Central
Paradigm
Maximize Minimize
beneficial effects complications
of treatment and risks
High-quality Cycle cancellation,
oocyte yield OHSS, multiple
pregnancy
Fauser BC et al: Predictors of ovarian response: progress towards individualized treatment in ovulation
Esteves, 6 induction and ovarian stimulation. Hum Reprod Update 2008;14:1-14.

7. Factors Determining Response
to Ovarian Stimulation
 Demographics and
anthropometrics (Age,
BMI, Race)
 Genetic profile
 Cause of Infertility
 Years of Infertility
 Health status
 Nutritional status
Esteves, 7

8. Level
1a
Female Age Negative
Duration of infertility Predictors
Basal FSH
Type of infertility All reflecting
Indication ovarian
reserve
Fertilization method
Number of oocytes retrieved Positive
Number of embryos transferred Predictor
Embryo quality
Esteves, 8 van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589.

9. Level
1a Use of Markers Pregnancy by number of oocytes
retrieved after mild (♦ ) or conventional
to Determine ( ) ovarian stimulation for IVF
Ovarian Reserve
⑤
Age ⑩
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-R
Verberg M et al. Hum Reprod Update 2009;15:5-12
Esteves, 9

10. Level
1a
AMH = AFC >Inhibin B >FSH >Age
Predictor
of Poor
Predictor of Excessive Response Response
● AFC studies
 AMH Studies
Predictor of
Pregnancy
In ART
● AFC studies
 AMH Studies
Broer et al. Hum Reprod Update 2011
Esteves, 10
Broer et al. Fertil Steril 2009

11. = remaining population of primordial and
resting follicles
Anti-Mullerian
Hormone levels
are correlated
with the
number of
follicles at
gonadotropin
independent
stage.
Esteves, 11
La Marca et al. Hum Reprod 2009

12. Level
1b Antral Follicle Count (AFC)
AFC alone on day 3 as a tool for
predicting the number of retrieved
oocytes in COS
= Number of antral
follicles present in
the ovaries at a given
time that can be
stimulated into
dominant follicle
growth by exogenous
Eldar-Geva et al. Fertil Steril 2005 gonadotropins
Esteves, 12 Devroey et al. Hum Reprod Update 2009

13. AMH and AFC
Anti-Mullerian Antral
Hormone Follicle
(ng/mL) Count
Cycle independent test; Simple and
Advantages
Intercycle stability inexpensive
Variation in test
No international assay interpretation and
standards for standardization;
Limitations
measurements (DSL & Moderate intercycle
Immunotech-Beckman) and interobserver
variability
Alviggi et al, Reprod Biol Endocrinol 2012; Broer et al, Hum Reprod Update 2011; Broekmans et al,
Fertil Steril 2009; Broer et al, Fertil Steril 2009; van Disseldorp et al, Hum Reprod 2010, La Marca
Esteves, 13 et al, Hum Reprod 2006; Hansen et al, Fertil Steril 2003; Elter et al, Gynecol Endocrinol 2005.

14. Markers of Ovarian Response
Antral Follicle Count (AFC)
Use a systematic process for counting antral follicles:
1. Identify the ovary.
Practical
2. Explore the dimensions in two planes (perform a scout sweep).
Recommendations for
3. Decide on the direction of the sweep to measure and count follicles.
Better Standardization:
● Cycle day 2-4
4. Measure the largest follicle in two dimensions.
A. If the largest follicle is ≤10 mm in diameter:
• Start to count from outer ovarian margin of the sweep to the
opposite margin. ● Count all AF 2-10mm
• Consider every round or oval transonic structure within the
ovarian margins to be a follicle. ● Real-time 2 dimension
• Repeat the procedure with the contralateral ovary. image adequate
• Combine the number of follicles in each ovary to obtain the AFC.
B. If the largest follicle is >10 mm in diameter: ● Transvaginal probe 7Mhz
• Further ascertain the size range of the follicles by measuring
each sequentially smaller follicle, in turn, until a follicle with a minimum
diameter of %10 mm is found.
• Perform a total count (as described) regardless of follicle
diameter.
• Subtract the number of follicles of >10 mm from the total follicle
count.
Esteves, 14
Broekmans et al., Fertil Steril, 2010; 94(3):1044-51

15. Use of Biomarkers to Individualize
Ovarian Stimulation Protocols
 COS should maximize treatment beneficial effects
(high-quality oocyte yield) and minimize risks
(cancellation, OHSS, multiple pregnancy).
 Significant predictive factors for pregnancy in IVF
are related to ovarian reserve.
 AMH levels and AFC accurately determine
ovarian reserve. Results can be used to guide the
choice of COS protocols.
 Both AMH and AFC have similar high accuracy to
predict which patients are at risk of excessive and
poor response to OS but should not be used to
predict the chances of pregnancy success.
Esteves, 15

16. What is in it for me?
Use of Biomarkers to Individualize Ovarian
Stimulation Protocols
Recent Advances in Injectable Gonadotropins
Preparations
 Rec-hFSH vs Urinary products
 GnRH Agonist versus Antagonist
 To whom to give rec-hLH? Differences between rec-hLH
and LH activity in HMG preparations?
Strategies to Improve Ovarian Stimulation
 Best Protocols to Minimize Risks and Reduce Dropout
Rates in IVF
Esteves, 16

17. • Incidence of Infertility (WHO II)
64%
• Prevalence of Infertile Patients
(WHO II) with PCO in Clinical
68% Practice
 OI, IUI, IVF
 Clomiphene Citrate
1st line in up to 56% of cases
Shift after an average of 3 cycles
 Injectable Gonadotropins
Esteves, 17 Reproductive Hormones Report - GCC Countries (Feb 2011)

18. Long-
r-hFSH r-hFSH acting
+r-hLH r-hFSH
u-FSH HP FbM
FbM
Pituitary r-hFSH
u-FSH
FSH
u-hMG
Horse Puriity
PMSG and
Safety, Quality,
Specific
Consistency and Patient
Activity
Convenience
1930s 1950 1980 1995 2003 2007 2010
Intramuscular administration sc Injector
pens
sc, subcutaneous; FbM, filled by Mass; HP, highly-purified
Esteves, 18
Adapted from Lunenfeld. Hum Reprod Update 2004;10:453–67

19. Level
1a
Meta-
analyses of Number Number
Statistical Clinical
rec-hFSH vs of RCTs of
significance significance
HMG/HP- included couples
HMG/uFSH
Coomarasamy 7 2,159 LBR (RR = 1.18, 95% CI: 4% difference in
et al, 2008 1.02 to 1.38, P<0.03) in LBR in favor of
favor of HMG HMG (CI: 1%-?)
Insufficient evidence
Al Inany et al,
6 2,371 of a difference in odds None
2009
of pregnancy or live birth
Van Wely et al, 28 7,339 Insufficient evidence None
2011 of a difference in odds
of live birth
Subgroup analysis of r- For a LBR of 25%,
hFSH vs HMG in favor of use of rFSH rather
HMG (OR 0.84, 95% CI than hMG would
0.72 TO 0.99; N=3,197) result in a LBR
19%-25%
Coomarasamy et al, Hum Reprod. 2008;23:310-5; Al Inany et al, Gynecol Endocrinol. 2009;
Esteves, 19 25:372-8; Van Wely et al. Cochrane Database Syst Rev. 2011; 2:CD005354

20. Purity Mean specific LH Injected
(FSH activity activity protein
content) (IU/mg protein) per 75 IU
(IU/vial)
(mcg)
hMG < 5% ~100 75 ~750
hMG-HP < 70% 2,000–2,500 75 ~33
rec-hFSH
Follitropin – 7,000–10,000 0 8.1
beta
Follitropin > 99% 13,645 0 6.1
alfa
Esteves, 20 Bassett et al. Reprod Biomed Online 2005;10:169–177.

21. Conventional FbM: Novel
Bioassay analitycal method
High
Protein content by
Rat ovary mass
weight variability
gain Minimal batch-to-
batch variability
(1.6%)
Urinary gonadotropins
Follitropin beta Follitropin alfa
Bassett et al. Reprod Biomed Online 2005;10:169–177;
Esteves, 21 Driebergen et al. Curr Med Res Opin 2003;19:41–46.

22. Level
1b
Number of Retrieved Oocytes by the
Same Dose of rec-hFSH vs HP-HMG
↑ 1.5 oocytes (GnRH antagonist cycles)
Devroey et al., 2012
↑ 3.1 oocytes (GnRH antagonist cycles)
Bosch et al., 2008
↑ 1.8 oocytes
MERIT Study, 2006
↑ 2.8 oocytes (GnRH agonist cycles)
Hompes et al., 2008
Devroey P et al, Fertil Steril. 2012;97:561-71; Bosch E et al, Hum Reprod. 2008;23:2346-51; Nyboe
Andersen A, et al. Hum Reprod. 2006;21:3217–3227; Hompes PG et al, Fertil Steril. 2008;89:1685-93 ;
Esteves, 22

23. Level
2a
Total Dose per Live Birth (IU)* Reproductive Biology and Endocrinology 2009; 7:111.
10,000
52.2% 9,690 To achieve a live
7,000 21.6% 7,739 birth, 21-52%
more HP-hMG
6,324* and hMG was
3,000
required
compared with
0
rec-hFSH HP-hMG hMG rec-hFSH
*Mean total dose per cycle/Live birth rate (≤35 years)
Esteves, 23

24. Rec-hFSH vs Urinary products
Overall, recombinant and urinary gonadotropins
have comparable clinical efficacy, but this
does not mean drugs are the same.
Recombinant preparations have 3 major
differences compared to urinary products:
 Higher purity and specific activity (SC delivery in
very small volumes))
 Higher dose precision (FbM)
 Higher potency (more oocytes retrieved)
Esteves, 24

25. Prevent
Can be
OHSS by
integrated in
GnRH-a
No flare spontaneous
GnRH antagonist and OI cycles Antagonist
effect with No hormonal
protocol administration
possible cyst withdrawal
formation Gonadotropin administration
Shorter
Can exclude duration of
early stimulation
pregnancy
Flare up Pituitary
effect suppression
Gonadotropin administration
Long GnRH
agonist Longer Agonist administration
protocol treatment
Pre-treatment cycle Treatment cycle
Esteves, 25

26. 1 2 3
pyro (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
GnRH
Antagonists
Mode of
Action
Esteves, 26

27. Why introduction of antagonists in
clinical practice has been slow?
Experience with Agonists
Why change if it is working
Clinicians’ concerns:
 Lower pregnancy rates
 Not been able to program
aspirations on weekdays
 LH surge (more monitoring)
 Difficult to use
Esteves, 27

28. Level
1a
Probability of Live Birth
N studies 45 22
Included IUI Yes No
cycles
N patients 7511 3176
Primary outcome OPR or LBR LBR
Odds-ratio 0.86 0.86
(95% CI: 0.69-1.08) (95% CI: 0.72-1.02)
1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.
Esteves, 28 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.

29. Pre-treatment with OCP 4 RCT; 847 patients
Days of stimulation +1.41 (+1.13; +1.68)
Level
Gonadotropin consumption (UI) +542 (+127; +956)
1a
No. oocytes retrieved 1.63 (-0.34; 3.61)
Pregnancy rate (%) 0.74 (0.53; 1.03)
Griesinger et al. Fertil Steril 2008; 90:1055-63
Flexible* (N=68) Fixed on Day 6 (N=72) P>0.05
Level 29.7 29.2 24.7 23.3
12.0 10.3
1b 9.7 9.9
Days of Dose No. Oocytes Pregnancy (%)
stimulation gonadotropin *LH >10 IU/L, and/or mean follicle >12 mm, and/or
(x75UI) serum E2 >150 pg/mL; No LH surge reported
Esteves, 29
Kolibianakis EM, et al. Fertil Steril. 2011; 95:558-62

30. Level
1b
Day of hCG administration
RCT ≥3 follicles of One day
normogonadotropic ≥16mm later P
women <40 yrs. on value
antagonist COH N=52 N=54
No. Metaphase II
6.1 ± 4.9 9.2 ± 7.1 .009
oocytes
Fertilization rate (%) 66.7 ± 23.4 70.1 ± 20.9 .44
Pregnancy rate (%) 34.6% 40.7% .55
Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.
Esteves, 30 Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.

31. Recent Advances in Gonadotropins
Preparations
GnRH Agonist versus Antagonist
Clinical Outcomes Evidence
No difference in probability of live birth 1a
(overall and subgroups) compared to
agonists
No difference in flexible or fixed GnRH 1b
antagonist protocols
OCP programming not detrimental 1b
Delaying hCG by 1 day not detrimental 1b
Esteves, 31

32. Normal
• ~80% normogonadotropic women (WHO II)
undergoing Ovarian Stimulation1-3
• 15-20% of NG women have less sensitive
ovaries
• Older patients (≥35 years)4
Low
• Poor responders5
• Slow/Hypo-responders6
• Deeply suppressed endogenous LH
(endometriosis)7
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.
Esteves, 32 RBMOnline 2009; 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637;

33. LH • Theca cells
Increase in LH
drive
LH • Granulosa
cells
Increase in FSH
drive FSH
Increasing the Number % Cycle Pregnancy
Level Stimulation Dose of oocytes cancellation rates
1b retrieved
FSH…
Manzi et al, 1994
Klinkert et al, 2004 …is not associated with better IVF
Berkkanoglu & Ozgur, 2010 outcome
Esteves, 33

34. Up to 45%
Infertility
Patients
• Older patients (≥35 years) aged 35 or
Less Sensitive Ovaries
• Poor responders above
• Slow/Hypo-responders
• Deeply suppressed endogenous LH (endometriosis)
Poor Responders* Hypo/Slow Responders
At least 2 of the following: Normal markers of ovarian reserve
Advanced maternal age (≥40 years) Hypo-responders:
Previous POR (≤3 oocytes with a d1-d7: normal initial follicullar recruitment
conventional stimulation protocol) using fixed starting dose of FSH; d7-
Abnormal ovarian reserve test (AFC<5; d10: plateau on follicullar growth
AMH <1.1) despite continuing same FSH dosage
Or: Slow responders:
2 episodes of POR after maximal High doses of FSH (>3,000UI) to promote
stimulation follicular growth;
May indicate genetic polymorphisms
of LH and/or FSH receptor
Marrs et al. Reprod Biomed Online 2004;8:175
De Placido et al. Clin Endocrinol (Oxf) 2004;60:637; Ferraretti et al. Fertil Steril. 2004; 82:1521-6;
Esteves, 34 Mochtar MH, Cochrane Database, 2007; Alviggi, et al. RBMOnline 2012

35. Level LH Supplementation in Poor
1a Responders…
Effect on
Regimen Outcome
Pregnancy
Mochtar et al, 2007
r-hFSH+rLH vs. OR 1.85
3 RCT (N=310) OPR
r-hFSH alone* (95% CI: 1.10; 3.11)
Poor responders
CPR RD: +6%,
Bosdou et al, 2012 r-hFSH+rLH vs. (95% CI: -0.3; +13.0)
7 RCT (N= 603) r-hFSH alone*
Poor responders LBR RD: +19%
(only 1 RCT) (95% CI: +1.0; +36.0%)
Hill et al, 2012
r-hFSH+rLH vs.
7 RCT (N=902) OR 1.37
r-hFSH alone CPR
Women advanced (95% CI: 1.03; 1.83)
age ≥35 yrs.
*long GnRH-a protocol; OR=odds-ratio; RD=risk difference
Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al,
Esteves, 35 Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.

36. Level LH Supplementation in
1b
Hypo/Slow Responders…
RCT 260 pts; “Steady” response on D8
(E2 <180 pg/mL; >6 follicles <10mm)
Mean No. oocytes retrieved IR (%) OPR (%)
40
32
22
18
14
10 9 11
6
FSH step-up (+150 UI) LH supplementation Normal Responders
(+150 UI)
Esteves, 36 De Placido et al. Hum Reprod. 2004; 20: 390-6.

37. Level To Whom to give LH
1b Supplementation in OI and IUI
LH levels 1.2 UI/L (WHO group I)
Higher follicular development pts. receiving LH (67% vs 20%;
p=0.02): Shoham, 2008.
Similar follicular development HMG vs FSH+rLH; higher
cumulative PR after 3 cycles in FSH+LH (56% vs 23%; p=0.01):
Carone, 2012.
WHO group II
Clomiphene-resistant: fewer intermediate-sized follicles and OHSS in
LH-supl. vs FSH group; similar ovulation rate (Plateau, 2006);
Previous over-response: higher monofollicular development in LH group
(32% vs 13%; p=0.04): Hughes, 2005;
IUI: higher monofollicular development in LH group without
intermediate-size (42% vs 11%; p=0.03); lower cycle cancellation due
to risk OHSS (-7% difference): Segnella 2011.
Esteves, 37

38. What is the optimal LH
supplementation protocol?
 Existing studies give us some clues but the
optimal LH protocol has yet to be established
 How much LH should be used?
 Should the dose be fixed or flexible?
 At what stage of the cycle should LH be
administered?
FSH
LH
2:1? 1:1? Fixed? Mimic of
natural LH levels?
Esteves, 38

39. Alfa Unit Beta unit Carboxyl terminal
(biological action segment
and receptor affinity) (determines half-life)
LH 92 AA; 121 AA Absent; half life of 20’
hCG Identical to LH 144 AA Present; half-life of 24h
Higher receptor affinity
Purity FSH LH activity
(LH content) activity (IU/vial) (IU/vial)
Rec-hLH >99% 0 75
Rec-hLH + rec-hFSH >99% 150 75
hMG-HP Unknown* 75 75*
*derives primarily from the hCG component, which preferentially is
concentrated during the purification process and sometimes was added
to achieve the desired amount of LH-like biological activity.
Esteves, 39 ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.

40. Level Differences in LH activity of rec-hLH
2a and HMG preparations
Matched case-control study;
N=4,719 pts.; long GnRH-a protocol
35
30 Duration of
P=0.02 31 Stimulation (days)
25
26 25 Mean No. oocytes
20 retrieved
15
IR (%)
10
5 CPR per transfer
(%)
0
2:1 r-hFSH+r- HMG rec-hFSH +
hLH HMG
Esteves, 40
Buhler KF, Fisher R. Gynecol Endocrinol 2011; 1-6.

41. Level
1a
Lower expression of LH/hCG receptor gene as well
as genes involved in in biosynthesis of cholesterol
and steroids in granulosa cells in pts. treated with
HMG preparations
May reflect down-regulation of LH receptors, as shown in animals:
Caused by a constant ligand exposure during the follicular
phase due to longer half life and higher binding affinity of
hCG to LHr
May explain the observed lower progesterone levels:
Caused by lower LH-induced cholesterol uptake, a decrease in
the novo cholesterol synthesis and a decrease in steroid
synthesis.
Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod
Esteves, 41
2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.

42. To whom to give rec-hLH?
Differences between rec-hLH and HMG preparations
 15-20% women have less sensitive ovaries
and worse outcomes in IVF.
 LH supplementation to OS is an evidence-
based strategy to maximize pregnancy results.
 LH activity in HMG is hCG-dependent:
hCG is concentrated during purification or added to achieve
the desired amount of LH-like biological activity.
 Lower expression of LH receptor gene in pts.
Treated with HMG (LHr down-regulation).
Preparations used are important for granulosa cell function
and may influence the developmental competence of the
Esteves, 42
oocyte and the function of corpus luteum.

43. What is in it for me?
1 Use of Biomarkers to Individualize Ovarian
Stimulation Protocols
Recent Advances in Gonadotropins Preparations
 Rec-FSH vs urinary products
 GnRH Agonist versus Antagonist
 To whom to give rec-hLH? Differences between rec-
hLH and LH activity in HMG preparations?
Strategies to Improve Ovarian Stimulation
 Best Protocols to Minimize Risks and Reduce Dropout
Rates in IVF
Esteves, 43

44. Strategies to Improve Ovarian
Stimulation
Up to 65% of couples dropout from IVF
without achieving pregnancy before they
complete 3 cycles
Reasons Pregnancy loss 94%
Psychological burden 49%-26% Unsuccessful cycle 87%
Prognosis 40%-23% Waiting after ET 81%
Waiting to find out how many 68%
Cost of treatment 23%-0% eggs fertilized
Relationship/divorce 15%-9% Result of pregnancy scan 47%
Physical burden 7-6%
Olivius K et al, Fertil Steril 2004;81:258; Land JA et al, Fertil Steril 1997; 68:278; Schroder AK, et al,
RBM Online 2004; 5:600; Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; Rajkhowa M et al,
Hum Reprod 2006; 21:358; Brandes M et al, Hum Reprod 2009; 24:3127; Hammarberg K et al, Hum
Esteves, 44 Reprod 2001; 16:374.

45. Level
2a
Patient Preferences
68% Easy of use 58%
Reasons
Dosing mechanism 43%
25% Less chance of error 26%
7%
Folitropin alfa Follitropin beta Needle-free
prefilled cartridge and reconstitution, • Allowed injections at
ready-to-use reusable pen conventional home
pen syringe
• Improved pts.
satisfaction (QOL)
Weiss N. RBMonline 2007;15:31-7
Esteves, 45

46. • Same injection device
design for all
gonadotropins;
• Color-coded for
differentiation;
• Pre-filled, ready-to-
use family of pens for
fertility treatment.
Esteves, 46

47. Esteves, 47

48. Level AMH and AFC to Determine
2a
Who is Who Prior to OS
Response to Anti- Antral False
Ovarian Mullerian Follicle Positive
Stimulation Hormone Count Rate
(ng/mL)
Risk of Excessive
Response (≥15 ≥ 3.5 > 15
oocytes or OHSS)
Risk of Poor ~15%
Response < 1.1 <5
(≤ 4 oocytes)*
pmol/L X1000/140
*Bologna criteria: Ferraretti et al. Hum Reprod 2011; Broer et al. Hum Reprod Update 2011;
Esteves, 48 Nelson et al. Hum Reprod. 2009; Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007.

49. Level Reduced Starting Doses of
2a
r-hFSH for Ovarian Stimulation in
High Responders
Clinical pregnancy rates/cycle
started
Individualized
60%
dosing in
50%
increments of 37.5 50.0%
IU of folitropin alfa 40%
possible by FbM 30% 35.3%
31.3% 31.1%
technology
20%
20.0%
Age (28-32) 10%
Oocytes retrieved 0%
75 IU 112.5 IU 150 IU 187.5 IU 225 IU
(8-12)
Esteves, 49 Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:95–204.

50. Level GnRH Antagonist Protocol in
1a
High Responders
9 RCT; 966 PCOS women Relative Risk
Duration of ovarian stimulation -0.74 (95% CI -1.12; -0.36)
Gonadotropin dose -0.28 (95% CI -0.43; -0.13)
Oocytes retrieved 0.01 (95% CI -0.24-0.26)
Risk of OHSS 20% vs 32%
Mild 1.23 (95% CI 0.67-2.26)
Moderate and Severe 0.59 (95% CI 0.45-0.76)
Clinical PR 1.01 (95% CI 0.88; 1.15)
Miscarriage rate 0.79 (95% CI 0.49; 1.28)
40% reduction in moderate/severe OHSS by using
antagonists rather than agonists
Esteves, 50 Pundir J et al. RBM Online 2012; 24:6-22.

51. Level
1b
Tailor OS in High Responders
by AMH (AFC)
Combination of Reduced rFSH Doses and
GnRH Antagonist
rec-hFSH 150UI AMH (ng/mL) >2.1
Agonist Antagonist
Days of Stimulation 13 (12-14) 9 (8-11)*
No. Oocytes retrieved (n) 14 (10-19) 10 (8.5-13.5)*
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
Esteves, 51 ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4):867-75.

52. Level GnRH Agonist for LH
1a Triggering in High Responders
 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.
11 RCT – 1,055 women
Moderate/
LBR OPR
severe OHSS
Fresh autologous OR 0.44 OR 0.45 OR 0.10,
cycles (8 RCT) (0.29 - 0.68) (0.31 - 0.65) (0.01 to 0.82)
Donor recipient OR 0.90 OR 0.91 OR 0.06
cycles (3 RCT) (0.57 - 1.42) (0.59 -1.40) (0.01 - 0.31)
Youssef et al. Cochrane Database Syst Rev. 2011
Esteves, 52

53. GnRH Agonist for LH
Triggering in High Responders
Challenge is to Rescue Luteal Phase Insufficiency.
Options are:
 Vitrification and FET in subsequent natural cycle
Level
vs coasting and Fresh ET same cycle
2b CPR: 50% vs 29% (P<0.05)
Garcia-Velasco, Fertil Steril, 2012
 Modified luteal support improved delivery rate:
Level hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses;
recLH; intense progesterone + estradiol; combined.
1b Delivery rates: 18% risk difference favoring hCG (before) X
6% (after modified luteal support).
Humaidan et al. Hum Reprod Update 2011.
Esteves, 53

54. 20092009
Cycles with GnRH
Antagonists 54%
Rec-hFSH 45%
15%
Rec-hFSH
+ HMG 43%
1999
2009
HMG 12%
Data supplied by REDLARA and ICMART
Esteves, 54

55. Evidence-based Strategies to Optimize
COS in Poor Responders
Esteves, 55

56. Level GnRH Antagonists in Poor
1b Responders
14 RCT (1,127 patients)
Duration of Number Cycle Clinical
stimulation Oocytes cancellation Pregnancy
retrieved
-1.9 days -0.17 1.01 1.23
(-3.6; -0.12) (-0.69; 0.34) (0.71; 1.42) (0.92, 1.66)
 Limited Clinical Benefit
Shortcomings:
- Definition of poor responders
- Different gonadotropins regimens for OS
Esteves, 56 Pu D et al. Hum Reprod. 2011; 26:2742.

57. Level
1a
Meta-analytic Effect on
Intervention Population
Studies Pregnancy
Kyrou et al,20091 Poor Higher LBR1,2,3
Growth Hormone Kolibianakis et al, 20092 responders Higher PR2
Duffy et al, 20103 Higher CPR3
Poor Higher LBR
Testosterone Bosdou et al , 2012
responders Higher CPR
Rec-hLH Mochtar et al, 20071 Poor Higher OPR1
supplementation Bosdou et al, 20122 responders1,2 Higher LBR2
to rec-hFSH Hill et al, 20123 Age ≥35 yrs3 Higher CPR3
Kolibianakis et al, Hum Reprod Update 2009,15:613-22; Kyrou et al, Fertil Steril̀ 2009;91: 749–66; Duffy et al,
Cochrane Database Syst Rev 2010;1:CD000099; Mochtar MH et al. Cochrane Database Syst Rev.
2007,2:CD005070; Bosdou JK et al, Hum Reprod Update 2012;8:127-45; Hill MJ et al. Fertil Steril
Esteves, 57 2012;97:1108-4.

58. Strategies to Improve Success by
Tailoring Ovarian Stimulation
Best Strategies to Maintain
Sustainable Pregnancy Results Evidence
and Minimize Complications in
“High” Responders
Low Starting Doses of r-hFSH, preferably 2a
filled by mass preparations
GnRH Antagonists 1a
Biomarkers to tailor OS 1b
GnRH Agonist for LH Triggering1 1a
1Associated with lower pregnancy rates
Esteves, 58

59. Best Strategies to Maximize
Pregnancy Results Evidence
and Minimize Complications in
“Poor” Responders
GnRH Antagonists (lower OS duration) 1a
Adjuvant Therapy 1a
Growth hormone 1a
Testosterone 1a
LH supplementation
Poor responders 1a
Advanced age (≥35) 1a
Slow/Hypo responders 1b
Esteves, 59

60. Consider a Change...
Esteves, 60