Workshop on Management of poor prognosis patients

MOBILE
BEST DATA PLANLorem Ipsum has two main statistical methodologies are used in data analysis which
summarizes data from a sample using indexes Tempor mediocrem imperdiet no usu,
tractatos salutatus ut est. Eu vel detraxit laboramus. Cu nam unum liber audiam.
Workshop on Management of Poor
Prognosis Patients
Dr. Matheus Roque
ORIGEN – Center for Reproductive Medicine – BRAZIL
Chennai –16/04/2017

What is our goal in Reproductive
Medicine?
The delivery of a healthy baby!
Case Discussion
+
EVIDENCE-BASED MEDICINE
The details can really make the difference!

Question #1
Have you ever heard about POSEIDON ?

POSEIDON GROUP
Created in 2015 (Carlo Alviggi_Itália)
Peter Humaidan
(Dinamarca)
Klaus Bühler
(Alemanha)
Robert Fischer
(Alemanha)
Alessandro Conforti
(Itália)
Sandro Esteves
(Brasil)
Claus Andersen
(Dinamarca)
Filippo Ubaldi
(Itália)
Founders:
Workshop on management of poor prognosis patients

The importance of the NUMBER / QUALITY of
oocytes
POSEIDON – New Concept
POSEIDON Group
Patient-Oriented Strategies Encompassing
IndividualizeD Oocyte Number
LOW PROGNOSIS PATIENTS
POSEIDON Group, Fertil Steril 2016

* Individualized treatment based on prognostic
categories
*Ability to retrieve the number of oocytes necessary to
obtain at least one euploid embryo for transfer in
each patient
oocytes
POSEIDON – New Concept

Question #2
What is hMG ?
It is a combo product with urinary FSH + LH
1. YES
2. NO
NO
hMG – urinary FSH + hCG

142 RCTs 2013 / 2014
800 combinations numerators and denominators
Live birth – only 22 studies
Wilkinson et al., Hum Reprod 2016

Conclusions
Standardize outcome reporting
IDEAL: LIVE BIRTH
Early outcomes (ovarian response or embryo quality)
Wilkinson et al., Hum Reprod 2016

Sunkara et al., Hum Reprod 2011
The importance of the number of oocytes

The importance of the number of oocytes
Sunkara et al., Hum Reprod 2011
16% to 21%
13% to 18%
8% to 12%
4% to 6%
 1 Oocyte
1 more oocyte up to 50%  LBR!!!

Smith et al., JAMA 2015
Cumulative live-birth across all initiated IVF cycles by age and oocytes
source
Prospective study
2003-2010
156,947 UK women
257,398 IVF cycles

How many oocytes ?
Thus, we really need
INDIVIDUALIZATION

INDIVIDUALIZATION
1. Identify the ideal number of oocytes / patient /
cycle
2. Obtain at least one euploid embryo / cycle

t2 t3 t4 t5 t8
cc1 cc2 cc3
s2 s3
Age
ICSI
Media
pH
Oxygen
Aneuploidy Viability?
Etiology
Temperature
Handling
Embryo Development
STIMULATION
Maturity
Courtesy Marcos Meseguer
DETAILS CAN MAKE THE DIFFERENCE
Factors controlling oocyte / embryo quality
Controlled Ovarian Stimulation

Case 1
• A 34-year-old patient was referred to your IVF center. The couple had a 2-year history of
infertility. Her body mass index was 21.1 kg/m2 and his was 29.2 kg/m2
• 1 IVF cycle 2016
• Regular menstrual cycle of 29-30 days;
• Ovarian Biomarkers – AFC – 14; AMH 2.12 ng/mL
• Seminal analysis (WHO 2010) – Oligoasthenozoospermia (Previous varicocelectomy with
improvements but still have [ ] < 10 million / mL; A+B = 22; A+B+C = 31; Kruger 5%)
AFC – 14 ; AMH 2.12 ng/mL

AMH vs. AFC
Magnusson et al, Hum Reprod 2017
Does the addition ofAMH to a conventional dosage
regimen, including age,AFC and BMI, improve the
rate of target ovarian response?

AMH vs. AFC
Magnusson et al, Hum Reprod 2017
Target Response
5-12 oocytes
Poor Response
0-4 oocytes
Hyper Response
>=13 oocytes
GONADOTROPIN STARTING DOSE
The addition of AMH:
1. DID NOT alter the rate of targeted ovarian response
2. DID NOT decrease the rate of OHSS
3. DID NOT decrease the cancelled cycles due to poor ovarian response

Case 2
2. In this case, what would be your gonadotrophin regimen? Why?
• a) r-FSH; starting dose of 100 IU
• b) r-FSH; starting dose of 125 IU
• c) r-FSH; starting dose of 150 IU
• d) r-FSH; starting dose of 225 IU
• e) A, B, C or D however with urinary
34 y.
Male factor infertility
1st IVF cycle
They opted for r-FSH. Why?

Recombinant vs. urinary

Esteves S., 2015

Driebergen et al., Curr Med res Opin 2003
160
180
200
220
240
260
280
300
225 IU
Urinary
Filled-by-bioassay
Recombinant
Filled-by-mass
225 IU
281 IU
180 IU
221 IU
229 IU
+25% / -20% +2% / -2%
FSH quantification

van Wely et al., Cochrane 2011
rFSH vs urinary gonadotrophins
OR 0.97 (95% CI: 0.86-1.08)
Recombinant vs urinary
Live birth (or ongoing pregnancy)

van Wely et al., Cochrane 2011
rFSH vs urinary gonadotrophins
OR 0.97 (95% CI: 0.86-1.08)
HOWEVER…
Live birth (or ongoing pregnancy)

Esteves et al., Reprod Biol Endocrinol 2009
GnRH agonist protocols
N=865
6,324 IU
7,739 IU
9,690 IU
Rec-FSH HP-hMG hMG
+22% +52%
IU of gonadotropin / live birth
- Rec-FSH lower dose / live birth
Total gonadotropin dose / live birth

Levi Setti et al., J Endocrinol Invest 2015
13 studies
- rFSH more oocytes vs. hMG
Number of retrieved oocytes

Recombinant vs Urinary
Total cost per live birth – fresh + frozen
cycles
Wex and Abou-Setta., Clin Econ Out Research 2013
hMG r-FSH hMG r-FSH hMG r-FSH hMG r-FSH

• rFSH vs urinary
- rFSH higher purity
- rFSH ↑retrieved oocytes
- ↓ total dose / live birth
Recombinant or urinary?

Case 2
• First IVF cycle
• 34 years old; AFC: 14; AMH 2.12 ng/dL
D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D13
End (mm) 3.4 4.1 5.1 6,7 7,1
Right
Ovary
<10 (6) <10 (6) 12,12,11, <10 (3) 14,13,13,
<10 (3)
17,15,15
<10 (3)
17,15,15
<10 (3)
Left Ovary <10 (8) 12, 11
<10 (6)
15,14,12 <10(5) 18,15,15,11
<10 (4)
19,17,17,
14
<10 (4)
19,17,17,
14
<10 (4)
Rec-FSH 225 225 225 225 300 300 300 300 300 300
Antag 1 1 1 1 1 1
Trigger
r-hCG
6-7 fols.
OR
+36h
6 retrieved oocytes -> 5 MII -> 4 - 2PN (80% FR) -> 2 GOOD Quality D+3
Luteal phase support d+2;
Fresh embryo transfer -> NEGATIVE
Total r-FSH 2700 IU = 450 IU/oocyte

Genro et al., Hum Reprod 2011
Antral follicle
(3-8mm) count (AFC)
at baseline
Pre-ovulatory follicle
(16-22 mm) count (PFC)
on dhCG
PFC x 100
AFC
FORT
Calculation
Follicular Output RaTe (FORT)
Sub-optimal / Hypo-responders
FORT

• 10%-15%ofpatients withnormalAFCandAMHwillpresent aninadequate
response
• Granulosa cellsHypo-sensitivity toFSH;Suboptimal response (4-9oocytes)
• Associatedwithhigher FSHdoses (>2,500IUFSH);lowerpregnancy rates
• Genomic profile->Polymorphisms (most commonFSHreceptor andv-betaAlviggi et al., Springer 2016
5º. – 6º. day
COS

36Laan et al., Curr Opin Endocrinol Diabetes Obes, 2012 Manna et al., Hum Mol Genetics, 2002
FSH receptor gene LHβ gene
Hormone Receptor Polymorphisms

37
Alviggi et al., RBM Online 2009
7.3
11.7
14.7
0
2
4
6
8
10
12
14
16
Group A (rFSH>3500
IU)
Group B (rFSH 2000-
3500 IU)
Group C (rFSH < 2000
IU)
n
No. Retrieved Oocytes
No. Retrieved Oocytes
31.8
6.7
0
0
5
10
15
20
25
30
35
Group A (rFSH>3500 IU) Group B (rFSH 2000-
3500 IU)
Group C (rFSH < 2000 IU)
%
% v-βLH
% v-βLH
Hormone Receptor Polymorphisms

Case 2
• First IVF cycle
• 34 years old; AFC: 14; AMH 2.12 ng/dL
D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D13
End (mm) 3.4 4.1 5.1 6,7 7,1
Right
Ovary
<10 (6) <10 (6) 12,12,11, <10 (3) 14,13,13,
<10 (3)
17,15,15
<10 (3)
17,15,15
<10 (3)
Left Ovary <10 (8) 12, 11
<10 (6)
15,14,12 <10(5) 18,15,15,11
<10 (4)
19,17,17,
14
<10 (4)
19,17,17,
14
<10 (4)
Rec-FSH 225 225 225 225 300 300 300 300 300 300
Antag 1 1 1 1 1 1
Trigger
r-hCG
6-7 fols.
OR
+36h
6 retrieved oocytes -> 5 MII -> 4 - 2PN (80% FR) -> 2 GOOD Quality D+3
Fresh embryo transfer -> NEGATIVE
HYPO RESPONSE
FORT 28.6%

Case 2
2. Now, in your IVF Center for a 2nd. IVF cycle, what would be your
gonadotrophin regimen? Why?
• e) r-FSH; starting dose of 600 IU
• f) add r-LH
• g) hMG
34 years old
Male factor infertility
2nd. IVF cycle
1st. COS with r-FSH
6 retrieved oocytes
2 d+3 good quality embryo
Fresh Embryo Transfer -NEGATIVEWe used r-FSH + r-LH (2:1) . Why?

Who needs LH supplementation ?

LH and Folliculogenesis
Courtesy from Dr Sandro Esteves

LH and Folliculogenesis
Courtesy from Dr Sandro Esteves
Who needs LH supplementation ?

Normogonadotrophic with slow / poor initial response
5º. – 6º. day
COS
FSH dose? + LH ?
Who needs LH supplementation?

Increased FSH LH supplementation
No of retrieved oocytes 5.87  2.3 11.3  6.91 De Placido et al., Human Reproduction, 2005
8.2 11.1 Ferraretti et al., Fertility and Sterility, 2004
6.1  2.6 9.0  4.3 De Placido et al., Human Reproduction, 2005
No of mature oocytes 4.7  1.6 7.8  4.3 De Placido et al., Human Reproduction, 2005
Implantation rate (%) 14.1 36.8 Ferraretti et al., Fertility and Sterility, 2004
10.5 14.2 De Placido et al., Human Reproduction, 2005
Pregnancy rate (%) 34.78 50 De Placido et al., Human Reproduction, 2005
22 40.7 Ferraretti et al., Fertility and Sterility, 2004
22 32.5 De Placido et al., Human Reproduction, 2005
Normogonadotrophic with slow / poor initial response

Hill et al., Fertil Steril 2013
Rec-LH in advanced maternal age
Implantation – OR 1.36 (1.05-1.78)
IMPLANTATION
Advanced Maternal Age
* Disclaimer: Lutropin alfa concomitantly administered with Follitropin Alfa for injection is indicated for stimulation of follicular development in infertile
hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L). Health authorities in India have not approved or supported the product
as safe and effective for the use addressed in the materials provided

CLINICAL PREGNANCY
Hill et al., Fertil Steril 2013
Rec-LH in advanced maternal age
Clinical Pregnancy – OR 1.37 (1.03-1.83)
Advanced Maternal Age

No. of retrieved oocytes
Number of Retrieved Oocytes
r-hFSH VS. r-hFSH + r-hLH
Lehert et al., Reprod Biol Endocrinol 2014
Rec-LH in POR
Retrieved oocytes– MD 0.75 (0.14-1.36)
Poor Ovarian Responders

Clinical Pregnancy
Lehert et al., Reprod Biol Endocrinol 2014
Clinical Pregnancy Rate
r-hFSH VS. r-hFSH + r-hLH
Rec-LH in POR
Clinical Pregnancy– RR 1.30 (1.01-1.67)

Humaidan et al., Hum Reprod 2017
ESPART study

ESPART study

• rFSH + rLH vs. rFSH
• No differences in general POR – Bologna criteria
* Disclaimer: Lutropin alfa concomitantly administered with Follitropin Alfa for injection is indicated for stimulation of follicular development in
infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L). Health authorities in India have not approved or
supported the product as safe and effective for the use addressed in the materials provided

BSC – Baseline Severity score

POOR OVARIAN RESPONDERS
BSC found to be an independent factor for live birth when tested by logistic regression analysis
r-FSH + r-LH r-FSH
BSC n (%) Live birth (%) n (%) Live birth (%)
0 (Mild) 170 (36.8) 18 (10.6) 156 (32.7) 34 (21.8)
1 (Moderate) 209 (45.2) 23 (11.0) 254 (53.3) 19 (7.5)
2 (Severe) 83 (18.0) 8 (9.6) 67 (14.0) 3 (4.5)
Overall 462 (100) 49 (10.6) 477 (100) 56 (11.7)

Indications for LH supplementation:
• Hypogonadotropic hypogonadism
• Hypo- / Suboptimal response
• Advanced maternal age (>35 years old)
• Moderate / Severe Poor Ovarian Responders

Case 2
• 2nd IVF cycle; 34y
• AFC: 14; AMH 2.12 ng/dL Trigger
r-hCG
14 fols.
OR
+36h
13 retrieved oocytes -> 12 MII -> 9 2PN (75% FR) -> 4 TOP / 2 NON-TOP Blastocyst (66.6% blast. Rate)
Single Embryo Transfer -> POSITIVE -> LIVE BIRTH (March/2017)
Total r-FSH 1650 IU = 126.9 IU/oocyte
rFSH+rLH 2:1

I will add LH, however...
Rec-LH or hMG ???

Rec-LH or hMG ???
Rec-LH = LH

Rec-LH or hMG ???
Rec-LH = LH
hMG = LH activity through hCG

Thus,
LH vs hCG

61
Anti-apoptotic effect
granulos
Up-regulation growth
factors
Act synergistically
IGF-1
Increase reponsiveness
FSH receptors
LH Activity

LH vs. hCG
Esteves and Alviggi, Springer 2015
LH vs. hCG – are there differences in embryo
quality?

The effect of stimulation protocols in embryo quality
Embryo Viability Assessment
Unpublished data - Marcos Meseguer
N= 319 ICSI cycles
• r-FSH + r-LH vs. hMG
* Disclaimer: Lutropin alfa concomitantly administered with Follitropin Alfa for injection is indicated for stimulation of follicular
development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L)’.
LH vs. hCG
Oocyte / Embryo Quality

N= 319 ICSI cycles
development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L)’.Unpublished data - Marcos Meseguer
LH vs. hCG

N= 319 ICSI cycles
• r-FSH + r-LH vs. hMG 0
2
4
6
8
10
12
14
hMG (n=1005) FSH+LH (n=427)
7.86
12.18
% of HIGH EMBRYOS p=0,035
*
LH vs. hCG

N= 319 ICSI cycles
% of HIGH quality embryos (Eeva) according to stimulation
protocols;
Logistic Regression analysis
Model effect values OR p value
Gonadotrophin FSH+LH vs. hMG 1.88 (1.17-3.02) 0.010
Oocyte recovered number 0.99 (0.97-1.03)
per oocyte
NS
Age Years 0.96 (0.97-1.03) NS
BMI Units 0.94 (0.94-1.02) NS
FSH+LH protocol produce 1.88 times more HIGH quality
embryos according to Eeva Algorithm
LH vs. hCG

LH vs hCG
Clinical evidence ?

Fábregues et al., Gynecol Endocrinol 2014
LH vs hCG
Clinical evidence

Bühler and Fischer, Gynecol Endocrinol 2012
LH vs hCG
Clinical evidence
development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH<1.2 IU/L)’.
0
5
10
15
20
25
30
35
No. Oocytes Implantation Rate Clinical Pregnancy Rate
9
19
31.3
7.8
13.9
26
%
r-hFSH + r-hLH (n=1,573) hMG (n=1,573)

Revelli et al, Reprod Biol and Endocrinol 2015
LH vs hCG
Pregnancy rate / embryo transfer vs. No. MII

Revelli et al, Reprod Biol and Endocrinol 2015
LH vs hCG
OR pregnancy

Case 1 - Messages
• LH is totally different from hCG
• rec-FSH + rec-LH is totally diferent from hMG
• FORT (FOllicular Output RaTe) – Pre-ovulatory follicle (>16mm) x 100
• Antral Follicle Count
• Sub-optimal / Hypo-responders (4-9 oocytes)
• Higher FSHconsumption
• GranulosacellsHypo-sensitivitytoFSH
• Genomicprofile->Polymorphisms
• Indications for LH supplementation:
• Advanced maternal age (> 35 years old)
• Moderate / Severe Poor Ovarian Responder

Case 3
• A 41-year-old patient was referred to your IVF center. The couple had a 3-year history of
infertility. Her body mass index was 24.1 kg/m2 and his was 23.2 kg/m2
• Left ooforectomy (cyst)
• Regular menstrual cycle of 28 days;
• Ovarian Biomarkers – AFC – 5; AMH 0.6 ng/mL
• Seminal analysis (WHO 2010) – Normal

POOR RESPONDERS - BOLOGNA CRITERIA
Ferraretti et al., Hum Reprod 2011
OR
≧40y
OR
follicles
2 of 3

Case 3
2. In this case, what would be your gonadotrophin regimen? Why?
• d) r-FSH + r-LH; starting dose 300 : 150 IU
• e) a, b or c with u-FSH
• f) hMG
41 y.
1st IVF cycle

Case 3
• 1st IVF cycle; 41y
• AFC: 5; AMH 0.6 ng/dL
5 retrieved oocytes -> 4 MII -> 3 2PN (75% FR) -> 2 Good Cleavage
Trigger
r-hCG
5 fols.
OR
+36h
What would you do now?

Case 3
• 1st IVF cycle; 41y
• AFC: 5; AMH 0.6 ng/dL
5 retrieved oocytes -> 4 MII -> 3 2PN (75% FR) -> 2 Good Cleavage
FRESH Double Embryo Transfer -> ONGOING PREGNANCY
Trigger
r-hCG
5 fols.
OR
+36h
We did a fresh embryo transfer

POOR RESPONDERS - BOLOGNA CRITERIA
Ferraretti et al., Hum Reprod 2011
OR
≧40y
OR
follicles
2 of 3
EvenBologna criteria canbeHETEROGENEOUS…
Decreasedoocytequality/increasedembryoaneuploidy

oocytes
NEW CONCEPT - POSEIDON
POSEIDON Group
Patient-Oriented Strategies Encompassing
IndividualizeD Oocyte Number
LOW PROGNOSIS PATIENTS

New concepts in ART: low prognosis patients
* Individualized treatment based on prognostic
categories
*Ability to retrieve the number of oocytes necessary to
obtain at least one euploid embryo for transfer in
each patient
oocytes
NEW CONCEPT - POSEIDON

POSEIDON
Low Prognosis Patients
YOUNG
Poor response
ADVANCED REPRODUCTIVE AGE
Poor response
YOUNG
Poor response
ADVANCED MATERNAL AGE
Poor response
GOOD OVARIAN RESERVE
POOR OVARIAN RESERVE

POSEIDON
*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 3
< 35 years
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
(AFC ≥5; AMH ≥1.2ng/mL)
*Group 4
≥35 years
(AFC<5; AMH<1.2 ng/mL)

*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
- LH supplementation: effective strategy
POSEIDON
LH Supplementation
POSEIDON 1 and 2
?

Iglesias et al, Fertil Steril 2014
Ethnicity and ovarian reserve / ovarian aging

Iglesias et al, Fertil Steril 2014
Prospective Cohort study; January-October 2012
Total gonadotropin (IU) 2,420  840 2,910  902 <.001
INDIAN WOMEN: 6-year advancement in ovarian aging
Sub-optimal response

Maalouf et al, BJOG 2016
United Kingdom (UK) Database
2000 to 2010: 38,709 women
Live birth rate and the effect of ethnicity

Multivariate analysis
If true biologic differences exist, they may profoundly affect
patient counseling and the adaptation of COS protocols to
biologic age rather than chronologic age
Iglesias et al., 2014

*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
Hypo- / Sub-optimal responders
- LH supplementation: effective strategy
Indian Women and POSEIDON

Indian Women and POSEIDON
*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
Hypo- / Sub-optimal responders
LH supplementation: effective strategy

*Group 3
< 35 years
*Group 4
≥35 years
- LH in a sub-group of POR (ESPART – Humaidan et al., 2017)
- GH?; DHEA?; Testosterone?; Letrozole?
- DuoStim? / Acu-oocytes or embryos?
POSEIDON
To add or not to add LH?
POSEIDON 3 and 4

*Group 1
<35 years
1a: <4 oocytes
1b: 4-9 oocytes
*Group 3
< 35 years
*Group 2
≥35 years
2a: <4 oocytes
2b: 4-9 oocytes
*Group 4
≥35 years
+ rec-LH
???

POSEIDON

oocytes
WHY POSEIDON?
POSEIDON Group
1. Stratification :QUALITY+QUANTITY
2. No ofoocytestoobtain atleast ONEEUPLOIDembryo ineachpatient
3. Patient expectations; workable plan toreducetheTime-to-pregnancy
4. Tailored therapeutic approach
5. Identify morehomogeneous populations forclinical trials
BETTER INDIVIDUALIZATION
*patient characteristics
*IVF center results

Take Home
MessageRec-LH IS COMPLETELY DIFFERENT FROM hCG
1 more oocyte up to 50% increase in LBR
POSEIDON - new concept (ability to retrieve oocytes to
achieve one euploid blastocyst
Rec-FSH: higher purity; ↑retrieved oocytes; improved
embryo quality than u-FSH
Rec-LH – POSEIDON 1 and 2
Indian women?

• LH is totally different from hCG
• rec-FSH + rec-LH is totally diferent from hMG
• FORT (FOllicular Output RaTe) – Pre-ovulatory follicle (>16mm) x 100
• Antral Follicle Count
• POSEIDON - new concept (ability to retrieve oocytes to achieve one euploid
blastocyst
• Indications for LH supplementation:
• Advanced maternal age (> 35 years old)
• Moderate / Severe Poor Ovarian Responder
• INDIAN WOMEN (POSEIDON 1 and 2)
Take Home
Message

To make our patients’ dream come
true…
The details can make the difference!

Thank you!
matheusroque@origen.com.br

Workshop on Management of poor prognosis patients

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