Principles and Practices of Individualized OI and IUI

1.
Principles
and
Prac-ces
of
Individualiza-on
in
OI/IUI
Sandro
C.
Esteves,
MD.,
PhD.
Medical
Director,
ANDROFERT
Andrology
&
Human
Reproduc=on
Clinic
Campinas,
BRAZIL

2. Learning
Objec-ves
1. Why
individualize
2. How
to
individualize
OS
3. How
to
individualize
triggering
4. How
to
individualize
luteal
support
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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3. Why
individualize?
Consulting &
diagnosis
Decide
treatment
strategy &
ovarian
stimulation
Planned
intercourse
or IUI
Treatment
outcome
Control Control Control
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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4. Maximize
beneficial
effects
of
treatment
Minimize
complica-ons
and
risks
Why
individualize?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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5. Top
3
clinical
dimensions
for
quality
improvement
in
infer-lity
care
• Effec-veness:
Technical
aspects
to
deliver
the
best
possible
outcome
(e.g.
pregnancy,
live
birth,
cumula=ve
LBR)
• Safety:
Complica=ons
(OHSS),
adverse
effects,
risks
(pa=ent
&
offspring),
errors/mistakes
• Pa-ent-­‐centeredness:
Informa=on
and
pa=ent
involvement,
competence
and
aPen=on
of
clinic
and
staff,
accessibility,
coordina=on
and
integra=on,
emo=onal
support
Dancet
et
al.
Hum
Reprod
2011;
Mainz
Int
J
Qual
Health
Care
2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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6. How
stakeholders
value
the
top
3
quality
dimensions
of
infer-lity
care
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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0%
50%
100%
Doctors
&
embryologists
Nurses
Pa-ents
Safety
Effec-veness
Pa-ent-­‐
centeredness
Dancet
et
al.
Hum
Reprod
2013

7.
Incidence1:
3-­‐6%
moderate
OHSS
~2%
severe
OHSS
Safety
1Aboulghar. Fertil Steril. 2012;97:523-6;
2Confidential Enquiry into Maternal and Child Health, 2007; 3ICMART
1.5
million
cycles/year3
~500
deaths
(last
10
years)
:
3/100,000
cycles2
OHSS
most
serious
complica-on
of
OI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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8.
OI/CC:
13.5%
of
mild
forms1
IUI:
2-­‐8%
cycle
cancella-on2
Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96;
Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356
OHSS
in
OI
and
IUI
Safety
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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9. OHSS
must
be
PREVENTED
rather
than
treated

10. Lack
of
psychological
support
and
poor
quality
of
service
~60%
treatment
discon-nua-on
22
studies
21,453
pa=ents
8
countries
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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11. Individualiza-on
is
a
quality
concept
Safety
Pa-ent-­‐
centeredness
Effec-veness
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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12. How
to
individualize?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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13. Individualizing
S-mula-on
Protocols
• Clinical
characteris-cs
• Ovarian
biomarkers
Iden-fy
who
is
who
• Pa-ent-­‐centered
• Effec-ve
• Safe
Protocol
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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14.
Young
and
aged
pa-ents
BMI
Polycys-c
ovaries
PCOS
Previous
OHSS
History
of
poor
response
Easily
Recognized
Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32;
Humaidan et al., Fertil Steril. 2010; 94:389-400.
Iden-fying
who
is
who
before
OS
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2015
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15.
The
Roderdam
Consensus
Polycys-c
ovary:
Ultrasound
showing
≥12
follicles
(2-­‐9
mm)
AND/OR
ovarian
volume
>10
cm3
Polycys-c
ovary
syndrome:
2
out
of
3
1.
Oligo-­‐
and/or
anovula=on
2.
Clinical
and/or
biochemical
hyperandrogenism
3.
Polycys=c
Ovary
OHSS
Risk:
PCOS
>
isolated
PCOS
characteris-cs
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.
Hum Reprod. 2004;19:41-7; Humaidan et al., Fertil Steril. 2010; 94:389-400
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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16. Not
easily
recognized
Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32;
Humaidan et al., Fertil Steril. 2010; 94:389-400.
BIOMARKERS
of
Ovarian
Response
Sensi-ve
and
aged
ovaries
Iden-fying
who
is
who
before
OS
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2015
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17. What biomarker do you value
more?
a. Basal FSH
b. AMH
c. AFC
d. Estradiol

18. AMH
~
AFC
>
FSH
>
Age
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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19. Popula-on
Cutoff
Sensi-vity
Specificity
Accuracy
AMH
ng/mL
High-­‐
responder1
2.1
85%
79%
0.82
Poor
responder2
0.82
76%
86%
0.88
*Beckman-­‐Couter
genera-on
II
assay;
1>20
oocytes
retrieved;
2≤4
oocytes
retrieved
Leão
RBF,
Nakano
FY,
Esteves
SC.
Fer5l
Steril
2013;
100
(Suppl.):
S16
AMH
&
AFC
should
be
internally
validated
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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20. 1Nardo
et
al.
Fer$l
Steril
2009;
2Checa
et
al.
Fer$l
Steril
2010
AMH
(ng/mL)
AFC
False
Result
Risk
OHSS1,2
>3.5
>16
~15%
pmol/L
X1000/140
Level
2a
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21. Quality-­‐based
individualiza-on
in
COS
High
responders*
Normal
responders*
Low
responders*
Clinical
features
&
Biomarkers
Safety
Pa-ent-­‐
centeredness
Effec-veness
*expected
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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22. 50
mg/d
100
mg/d
150
mg/d
Ovula-on
Ovula-on
2
–
3
cycles
with
the
same
dose
Ovula-on
No
Ovula-on
No
Ovula-on
No
Ovula-on
No
pregnancy
Subop-mal
Endometrium
(thickness
<7mm)
Injectable
Gonadotropins
Clomiphene
Citrate
Hypogonadotropic
hypogonadism
&
hypergonadotropic
hypogonadism
Anovula-on:
how
many
cycles
and
how?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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23. CC
–
ASRM
Prac-ce
Guidelines
2013
• No
indica-on:
– Low
ovarian
reserve
– severe
male
factor
infer-lity
– Tubal
pathology
• Anovulatory
women
who
ovulate
with
CC:
– PR
>50%
in
6
cycles;
lower
in
obese
(~16%)
• Therapy
beyond
6
cycles
not
recommended
ASRM
Prac=ce
CommiPee.
Fer$l
Steril
2013;100:343–8
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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24. How to individualize use of
injectable gonadotropins and
what to expect?

25. ASRM
Prac-ce
Guidelines
2008
• Pre-­‐Tx
evalua-on:
– Thyroid
func-on
and
hyperprolac-nemia
– HSG,
TVUS
– Semen
analysis
• Low
dose-­‐gonadotropin
(37.5-­‐75
IU/day)
• Monitoring:
TVUS,
E2
levels
• Ovula-on
trigger:
hCG,
GnRHa
• Luteal
phase
support
recommended
ASRM
Prac=ce
CommiPee.
Fer$l
Steril
2008;90:S7-­‐12
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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26. Where
to
do
it?
• ISO
9001
cer-fied
Andrology
lab
• External
QC
Semen
parameters:
Sperm
count
&
mo=lity
Morphology
&
vitality
Leukocyte
count
Post-­‐washing
mo=le
sperm
count
Sperm
DNA
fragmenta=on
Expanded
Semen
Analysis
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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2015
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27. Where
to
do
it?
Semen
parameters:
Morphology
>4%
(strict
criteria)
Leukocytes
<
1
million/mL
(Endtz
test)
Post-­‐processing
total
sperm
count
>5
million
Ø
2-­‐layer
discon=nuous
coloidal
gradient
(Isolate)
Ø
Swim-­‐up
method
Sperm
DNA
fragmenta-on
(SCD)
<20%
Semen
criteria
for
OI/IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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28. Strict
morphology
≤4%
>4%
Montanaro-­‐Gauci
et
al.
(2001)
2.6%
15.6%
Ombelet
et
al.
(1997)
12.1%
16.5%
Karabinus
and
Gelety
(1997)
6.5%
9.0%
Lindheim
et
al.
(1996)
1.0%
19.5%
Toner
et
al.
(1995)
7.0%
11.3%
Matorras
et
al.
(1995)
10.9%
13.0%
PR
per
cycle
8.7%
(64/731)
12.8%
(208/1628)
P
<0.001
Predic-ve
value
of
normal
sperm
morphology
(WHO
2010)
for
IUI
Adapted
from:
J
Van
Waart,
TF
Kruger,
CJ
Lombard
et
al.
Predic=ve
value
of
normal
sperm
morphology
in
intrauterine
insemina=on
(IUI):
a
structured
literature
review.
Hum.
Reprod.
Update
(2001)
7:495-­‐500
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29. 19%
1.5%
Normal Elevated
Live Birth Rates with
Intrauterine Insemination
OR = 0.07
[95% CI: 0.01-0.48]
Feijo & Esteves Fertil Steril 2014;101:58-63
ART Outcome in Men with High Sperm DNA
Damage
Predic-ve
value
of
normal
sperm
DNA
fragmenta-on
for
IUI
Normal
values
<20%
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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Bungum et al. Hum Reprod 2007; 22: 74–9

30. CC/TMX/AI
+
injectable
gonadotropin
CC
D2-­‐D7
+
50-­‐75
IU
gonadotropin
D8
on
Injectable
gonadotropin
alone
D2/D3
variable
star-ng
doses
HMG,
uFSH
rec-­‐hFSH
Protocols
with
gonadotropins
in
OI/IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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31. Our
method
in
OI/IUI:
low
dose
step-­‐up
gonadotropin
alone
s-mula-on
• Star-ng
dose:
37.5
-­‐
50
IU
(rec-­‐hFSH
pen
injec-on)*
• Step-­‐up
(by
12.5
to
37.5
IU)
if
no
follicles
>10mm
auer
7
days
• Step-­‐up
every
7
days
un-l
dominant
follicle
appear
• Rec-­‐hCG
(250
mcg):
≥18mm
and
endometrium
≥7mm
• LPS:
progesterone
gel
90
mg
once/day
2
3
4
5
7
6
8
9
10
11
12
13
1
Ultrasound
Menses
Start
day
14
15
*Menormin
added
in
PCO
pa=ents;
Medroxiprogesteron
10
mg/d
to
induce
menses
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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32. • N
=
968
cycles
• >70%
ovulatory
cycles;
>85%
monofollicular
growth
• Threshold
to
produce
a
dominant
follicle:
Ø 37.5
to
75
IU
(~75%)
• Average
s-mula-on
dura-on:
15
days
• CPR
auer
6
cycles:
~60%
(WHO
type
II)
• IUI
auer
3
cycles:
28.7%
(cervix,
idiopathic,
male)
• No
moderate/severe
OHSS
• ~10-­‐15%
cancella-on
(mul-follicular
development)
Low
dose
step-­‐up
gonadotropin
alone
s-mula-on
in
anovulatory
WHO
II
pa-ents
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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33. Prac-cal
aspects
in
low-­‐
dose
gonadotropin
treatment
Be
pa-ent!
It
may
take
10
days
or
more
for
a
dominant
follicle
to
appear
during
the
first
treatment
cycle
TVUS
scan
before
star-ng:
progestin (medroxyprogesterone acetate, 5-10 mg/d)
to induce a withdrawal bleed if endometrium thickness
>8 mm
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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34. Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356
No.
Studies
No.
Par-cipants
Odds-­‐ra-o
Pregnancy
7
556
OR:
1.76
(95%
CI:
1.16
to
2.66)
Miscarriage
4
120
OR:
1.2
(95%
CI:
0.67
to
1.9)
Mul-ple
Pregnancy
4
120
OR:
0.73
(95%
CI:
0.32
to
1.67)
OHSS
2
200
OR:
4.44
(95%
CI:
0.48
to
41.25)
Level
1a
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35. Conven-onal
vs
low
dose
step-­‐up
s-mula-on
in
IUI
Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356
2
RCT;
n=
297
≥75
IU/day
50-­‐75
IU/
day
OR
OHSS
13%
2.7%
5.52
(95%
CI:
1.85-­‐16.52)
Pregnancy
31.1%
28.2%
1.15
(95%
CI:
0.69-­‐1.92)
Level
1a
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36. Level
1a
3
RCT;
“equal
dose
group”
Higher
PR
with
rec-­‐hFSH
(16.4%
vs
12.3%)
RR: 1.39 (95% CI: 1.00-1.96)
Meta-­‐analysis
6
RCT
(N=713
pts;
1,581
cycles)
Recombinant
X
urinary
gonadotropins
in
IUI
Similar
PR:
14.5%
vs
14.9%
but
rec-­‐FSH
dose
50%
lower
(RR:
0.970;
95%
CI:
0.68-­‐1.37)
Can=neau
et
al.
Cochrane
Database
Syst
Rev.
2007;
18(2):CD005356
37.5
62.5
50
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37. LH
supplementa-on
in
WHO
group
I
(LH levels <1.2 UI/L)
Higher
follicular
and
endometrial
development
pts.
receiving
LH
(67%
vs
20%;
p=0.02)
Shoham et al., 2008
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38. Clomiphene-­‐resistant
Fewer
intermediate-­‐sized
follicles
and
OHSS
in
LH-­‐supl.
vs
FSH
group;
similar
ovula-on
rate
(Plateau,
2006)
Previous
Excessive
Response
Higher
monofollicular
development
in
LH
group
(32%
vs
13%;
p=0.04)
Hughes
et
al.,
2005
IUI
Higher
monofollicular
development
in
LH
group
w/o
intermediate-­‐size
(42%
vs
11%;
p=0.03);
Lower
cycle
cancella-on
due
to
OHSS
risk
(-­‐7%
difference)
Segnella
et
al.,
2011
LH
supplementa-on
in
WHO
group
II
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39. 1. PCOS
w/previous
excessive
response
to
FSH
75
IU
rec-­‐LH
from
D1
(min.
7
days)
2.
Hypo-­‐hypo
75
IU
rec-­‐LH
from
D1
3.
Poor
responders;
advanced
age
(>35
yr.)
Rec-­‐FSH
+
rec-­‐LH
(2:1
ra=o)
from
Sd1
(225
IU/day)
2
3
4
5
7
6
8
9
10
11
12
13
1
Ultrasound
Menses
14
15
Our
method
of
LH
supplementa-on
in
OI/IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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40. Gonadotropins
containing
LH
ac-vity
Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.
Product
LH
ac-vity
(IU/
vial)
LH
content*
Purity
hMG
75
hCG
~5%
HP-­‐hMG
75
hCG
~70%
Lutroprin
alfa
(rec-­‐hLH)
75
LH
>99%
2:1
Follitropin
alfa
+
Lutroprin
alfa
(rec-­‐hFSH
+
rec-­‐hLH)
75
LH
>99%
*hCG
concentrated
or
added
during
purifica-on
process
(8IU
hCG
~
75IU
LH)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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41. HMG:
lower
expression
of
LH
receptor
and
other
genes
involved
in
steroids
biosynthesis
in
GC
Down-­‐regula5on
due
to
constant
ligand
exposure
of
receptors
to
hCG
Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod
2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Func-onal
and
molecular
differences
in
prepara-ons
with
LH
ac-vity
HMG
vs
FSH+recLH
in
WHO I
Similar
follicular
development
but
higher
PR
auer
3
cycles
in
rec-­‐LH
group
(56%
vs
23%;
p=0.01)
Carone
et
al.,
2012
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ANDROFERT

42. Beta unit
Carboxyl
terminal
segment
Longer in
hCG
Higher
receptor
affinity in hCG
Absent in LH
and present
in hCG
Longer half-life in
hCG
Sources of LH
Leao & Esteves. Clinics 2014; 69(4): 279–293.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

43. Divergence in receptor-mediated
signaling between LH and hCG
Choi & Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

44. LH
and
hCG
elicit
different
gene
expression
LH
hCG
LHR
and
FSHR
expression
(Trafficking
of
re=noic
acid
:
RXRB,
TTR,
ALDH8A1)
Meiosis
and
follicular
matura-on
(TRA
:
RXRB,
TTR,
ALDH8A1;
IL11;
AKT3)
Follicular
development
(IL11;
AKT3)
Cellular
growth
(RXRB,
TTR,
ALDH8A1;
IL11;AKT3)
Ovarian
stereodogenesis
(TRA
:
RXRB,
TTR,
ALDH8A1)
Embryo
development
&
survival
(AKT3)
Aromatase
inhibi-on
(PPARS)
Apoptosis
enhancement
(DNAsi)
LH
hCG
Grondal ML et al. Fertil Steril 2009; Menon KM et al. Biol Reprod 2004;; Ruvolo et al. Fertil Steril 2007
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

45. Injectable
gonadotropins:
when,
how
and
what
to
expect?
Injectable
gonadotropins
when…
§ 3
CC
ovulatory
cycles
but
no
pregnancy
§ Subop-mal
endometrium
thickness
or
no
response
w/CC
§ WHO
I
(hypo-­‐hypo)
anovula-on
Low-­‐dose
step-­‐up
is
the
best
protocol
Higher
PR
than
CC
without
increased
risks
Higher
potency
and
efficacy
w/recombinants
LH
supplementa-on
mandatory
in
WHO
I
and
beneficial
in
selected
WHO
II
pa-ents
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

46. How to individualize ovulation
trigger in OI and IUI cycles?

47. 14h
14h
20h
48h
0
20
h
Natural
LH
surge
hCG
Adapted
from
Chan
et
al.
Hum
Reprod.
2003;18:2294-­‐7
Day
6
Both
hCG
and
GnRHa
used
to
trigger
ovula-on
as
surrogates
for
the
mid-­‐cycle
LH
surge
GnRHa
36-48 h
Day
8
Rescues CL, maintaining
luteal function until
placental steroidogenesis
is well established
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

48. When:
Ø
mean
diameter
dominant
follicle
2D
TVUS
23-­‐28
mm
(988
IUI
with
CC
&
tetrozole)2
≥16
mm
(620
IUI
with
gonadotropins)3
~19
mm
(615
IUI
with
gonadotropins)4
hCG for triggering ovulation
1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; 2Palatnik et al, Fertil Steril
2012;97:1089–94; 3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60; 4Shalom-
Paz E et al. Gynecol Endocrinol. 2014;30:107-10; 5Andersen et al. Hum Reprod 1995;10:3202–5
Ovula-on
occurs
38.3
±
0.54
h
later5
Ø
-med
intercourse
and
IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

49. Why
do
some
pa-ents
fail
to
ovulate
auer
hCG
injec-on?
1. Errors
hCG
administra-on
2. Type
of
hCG
3. LH
receptor
deficiency
4. Blood/intrafollicular
level
barely
achieved
5. Not
enough
-me
for
intrafollicular
hCG
ac-on
Most
stable
gonadotropin*
*temporary changes in refrigeration chain
do not affect bioactivity
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

50. Urinary
Recombinant
Timelines
1948
2001
Ac-ve
protein
30%
>99%
Other
proteins
70%
None
Bioac-vity
800
IU/mg
27,000
IU/mg
Half-­‐life
30
h
29.6
h
Presenta-on
lyophilized
vials
(5,000-­‐10,000
IU)
pre-­‐filled
syringe
and
pen
device
(250
mcg
≅
6,750
IU)
Route
IM
SC
ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; Tsoumpou et al. Reprod Biomed Online.
2009;19:52-8
hCG for triggering ovulation
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

51. 250 μg rhCG=6,750 IU; SC
10,000 IU uhCG; IM
5,000 IU uhCG; IM
SerumhCGlevels
Trinchard-Lugan et al., 2002
Itskovitz et al., 1991
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

52. Propor-on
of
total
immunoreac-vity
(%)
Pregnyl®
Choragon®
Profasi®
Ovitrelle®
Intact
bioac-ve
hCG
50
30
96
>99
Hyperglycosylated
hCG
0.6
4
0.5
<0.1
Free
β
subunit
6.2
8
2.4
<0.1
β-­‐core
fragment1
43
58
1.2
-­‐-­‐
Epidermal
growth
factor2
181-­‐204
154
4-­‐10
-­‐-­‐
Gervais et al. Glycobiology 2003;13:179-89; Yarram et al. Fertil Steril 2004;82:232-3
1degradation product of hCG;
2EGF is a contaminant (ng/5000IU)
Func-onally
intact
hCG
and
contamina-on
in
urinary
formula-ons
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

53. Treatment: Profasi 500 r-hCG 250 r-hCG
MaximumhCHperpatient
0
300
600
900
BMI
15 25 35
Weight (kgs) 55 64 90
Blood volume (lts) (7% of weight) 3.8 4.4 14
Fat (kgs) (essential 13.5% of weight) 7.4 8.6 27
hCG Blood Threshold
hCG Intrafollicular Threshold
Blood represents about 7% of the body mass or about 4.5 kg
(volume ~ 4.4 liters) in a 64 kg (141 lb) person." Cameron, J.. Physics of the
Body. 2nd Edition. Madison, WI:, 1999: 182.
Injec-ng
hCG:
size
and
BMI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

54. Markle et al. Fertil Steril 2002; 78:71-2
4.4%
10.8%
15.2%
Timing
Recons=tu=on
or
Injec=on
technique
Total
%
Errors
(N=65)
Human
errors
auer
urinary
hCG
administra-on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

55. Clinical
efficacy:
u-­‐hCG
vs
rec-­‐hCG
RCT
N
Odds-­‐ra-o
Live
birth
6
1,019
OR:
1.04
(95%
CI
0.79
to
1.37)
Miscarriage
7
1,106
OR:
0.69
(95%
CI:
0.41
to
1.18)
Severe
OHSS
3
549
OR:
1.49
(95%
CI:
0.54
to
4.1)
Side
Effects
3
374
OR:
0.39
(95%
CI:
0.25
to
0.61)
Level
1a
Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.
Similar,
but
fewer
side-­‐effects
with
rec-­‐hCG
Recommended
Dose
OI/IUI:
5,000
IU
(u-­‐hCG)
and
250
mcg
(rec-­‐hCG)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

56. hCG
preferences
in
treatment-­‐
experienced
pa-ents
at
Androfert
Total
(n=76)
60%
29%
3%
8%
prefer
new
pen
prefer
pre-­‐filled
syringe
prefer
lyophilized
powder
to
recons=tute
Not
maPer
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

57. ü Beder
safety
profile
ü Beder
tolerated
ü Easy
to
teach
pa-ents
ü Pa-ent-­‐friendly
• Easy
to
handle
• More
convenient
(self-­‐injec=on)
Rec-­‐hCG
pen
injector
method
of
choice
for
hCG
administra-on
at
Androfert
Pa-ent-­‐
centeredness
Effec-veness
Safety
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

58. hCG stimulates granulosa-lutein cells to produce vascular
endothelial growth factor (VEGF)1,2
VEGF binds to VEGFR-2 on the endothelial cell membranes
leading to increased vascular permeability, causing OHSS1,2
Risk factors for OHSS2,3:
Multifollicular development
Estradiol ≥ 5,000 ng/L
1Soares, et al., Hum Reprod Update 2008, 14:321; 2Fiedler & Ezcurra Reprod Biol Endocrinol
2012,10:32;3Papanikolaou et al. Fertil Steril 2006, 85:112–120
Alternatives: Cancellation or IVF w/GnRH agonist
When
to
avoid
hCG
administra-on
in
OI/IUI?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

59. hCG
x
GnRH
agonist
as
surrogates
for
mid-­‐cycle
LH
surge
in
IUI
Meta-­‐analysis
(3
RCT;
N=180)
Pregnancy
rate:
OR
1.27
(0.68-­‐2.40)
Cantineau et al. Cochrane Database Syst Rev. 2010(4):CD006942
14h
14h
20h
48h
0
20h
4h
GnRHa
Natural
LH
surge
Luteal
phase
defect
Our preference:
§ 0.2 mg triptorelin SC
§ Same criteria hCG administration
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

60. hCG
and
GnRHa
surrogate
for
mid-­‐cycle
LH
surge
Rec-­‐hCG
equivalent
efficacy
and
beder
safety
and
tolerability
profile
than
u-­‐hCG
Type
of
hCG,
human
errors
and
BMI
should
be
considered
in
pa-ents
who
fail
to
ovulate
Ovula-on
trigger
in
OI/IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

61. How to individualize luteal
phase support in OI and IUI
cycles?

62. Progesterone
cri-cal
for
endometrial
recep-vity
q Prepares
endometrium
for
implantation
q Maintains
pregnancy
q May help
prevent
miscarriage
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

63. Corpus
luteum
func-on
dependent
on
pulsa-le
LH
release
from
pituitary
Mid-­‐cycle
LH
levels
Natural
cycle
6.0
IU/l
hCG
trigger
0.2
IU/l
GnRHa
trigger
1.5
IU/l
Tavaniotou & Devroey, 2003; Humaidan et al. 2005
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

64. Ovulation
hCG
Day 8
Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991;
Weissman et al., 1986 ; Bonduelle et al., 1988
Day 6.5
Trigger
hCG
LH activity deficiency period
GnRHa
28-32 hours
Early
luteal
phase
auer
hCG
and
GnRHa
triggering
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

65. LPS
mandatory
in
IVF
s-mulated
cycles
• hCG
vs.
Placebo
or
No
treatment:
Higher
ongoing
PR
(OR=1.75; 95% CI: 1.09-2.81)
• Progesterone
vs.
Placebo
or
No
treatment:
Higher
clinical
PR
(OR=1.83; 95% CI: 1.29-2.61)
Higher
ongoing
PR
(OR=1.87; 95% CI: 1.19-2.94)
Higher
live
birth
rates
(OR=2.95; 95% CI: 1.02-8.56)
Level
1a
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

66. P routes & types Evidence Effect Conclusion
Vaginal as effective
as IM/oral
13 RCT; 2
MA; >2,000
cycles
Similar CPR, LBR
& miscarriage True
Vaginal safer and
more patient-
friendly than IM/oral
3 RCT; 1
MA; >2,000
cycles
Lower side effects;
Increased patient
satisfaction
True
Among vaginal P,
patients prefer gel
7 RCT; 1
MA; >2,400
cycles
Easier to use;
better adherence;
lower discharge
True
Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010;
van der Linden et al Cochrane 2011
Evidence
on
LPS
in
s-mulated
cycles
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

67. Our
method
in
OI/IUI:
vaginal
progesterone
gel
• Single
daily
administra-on
(90
mg
P)
hCG
cycles:
Begin
2
days
post-­‐hCG
administra=on
(OI)
or
day
of
insemina=on
(IUI)
GnRHa
cycles:
Same
vaginal
P
regimen
+
hCG
bolus
(~1000
IU)
day
insemina=on
• If
pregnancy
occurs,
con-nue
P
for
10
weeks
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

68. 1
hour
3
hours
2
hours
4
hours
Time
Bioadhesion of vaginal P is essential
because it takes ~4h to reach steady
state in the uterus (first-pass effect)
Bulletti C et al. Hum Reprod 1997
aqueous
lipid
-ssue
micronized
progesterone
in
an
‘oil-­‐in-­‐water’
emulsion
(Crinone®
8%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

69. 0
5
10
15
20
25
30
35
40
IM P Vaginal P
ng/mL
Endometrial Levels
0
0.5
1
1.5
2
2.5
3
3.5
IM P Vaginal PngP/mgprotein
Serum Levels
P<0.0001
P<0.0001
Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3
P in oil (50mg) vs. Crinone 8% (90 mg)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

70. Luteal-­‐placental
shiu
on
P
produc-on
occurs
around
7-­‐12th
gesta-onal
week
0
100
200
300
400
500
600
700
800
900
0
10
20
30
40
50
60
70
80
4 5 6 7 8 9 10
E2(pg/mL)
P(ng/mL)
Gestational age in weeks P E2
Scott et al. Fertil Steril 1991; 56:481
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

71. Principles
and
Prac-ces
of
Individualiza-on
in
OI/IUI
Conclusions
• Individualiza-on
is
a
quality
concept
• Safety,
effec-veness
and
pa-ent-­‐centeredness
are
important
principles
in
a
quality-­‐based
individualized
infer-lity
care
• Novel
biomarkers
combined
with
new
devices
&
drug
regimens
can
be
used
to
deliver
a
high
quality
evidence-­‐based
individualized
OI/IUI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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ANDROFERT

72. Thank
you
‫ا‬‫شكر‬ Obrigado
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presenta-on
is
available
at
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sandroesteves