7. Having
Difficulty
Conceiving
1Boivin J, et al. Hum Reprod 2007;6:1506; 2ObGyn Research 2003, EMD Serono;
3Domar AD. Fertil Steril 2004;81:271
Treated
by
Infertility
Specialist
20% stop treatment before finishing
clomiphene citrate (CC)2
23% complete CC and then stop2
45% never seek the doctor1 100
Treated by
ObGyn
55
31
25-40% consult but never start
treatment2
60-65% drop out before completing
treatment3
20
8
8. Esteves, 8
Shift of Fluid from Intravascular to Third Space
hCG
Vascular Permeability
Intravascular Volume
Depletion and
Haemoconcentration
Extravascular Transudate
Accumulation
No direct vasoactive
activity
Vasoactive
Substances
VEGF
Aetiopathogenesis
Albert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037;
Gómez et al. Endocrinology. 2002;143:4339
9. Esteves, 9
VascularEndothelial
GrowthFactor
1Yan et al, J Clin Endocrinol Metab 1993; 77:1723; 2Neulen et al, J Clin Endocrinol Metab
1995; 80:1967; ; 3Wang et al, J Clin Endocrinol Metab 2002; 87:3300;
4Pellicer et al, Fertil Steril 1999; 71:482;
Induces endothelial cell proliferation
Increases capillary permeability
VEGF and OHSS:
• VEGF is expressed in human ovaries1
• VEGF mRNA expression increases in
granulosa cells after hCG administration2,3
• Elevated VEGF levels in serum, plasma, and
peritoneal fluids4
10. Esteves, 10
Early onset Late onset
Lyons CA et al., Hum Reprod 1994, 9:792.; Mathur RS, Fertil Steril 2000, 73:901;
Papanikolaou et al.,Hum Reprod. 2005; 20:636.
ClinicalAspects
Exogenous hCG
administered for final
oocyte maturation
Endogenous hCG
produced by
implanting blastocyst
3–7 days after hCG 12 -17 days after hCG
Predicted by high number
of growing follicles and
elevated E2 levels
Predicted by number of
gestacional sacs
(multiple pregnancy)
Higher risk of preclinical
miscarriage
More likely to be
severe
11. Esteves, 11
ClinicalAspects
Severity of symptoms, signs and
laboratory findings
Rabal et al., 1967
Schenker and Weinstein, 1978
Golan et al., 1989
Navot et al., 1992
Rizk & Aboughar, 1999
12. Esteves, 12
Abdominal
distension/
discomfort
Mild nausea,
vomiting
Diarrhea
Enlarged
ovaries
No relevant
laboratorial
alteration
Lacking clinical
significance
Fiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32
OHSS-Classification
Similar to Mild +
Ascites
Hct >41%
WBC >15,000
Hypoproteinemia
Require careful
monitoring
Intractable nausea/vomiting
Severe dyspnea; Hydrothorax
Oliguria/anuria; Tense ascites
Low central venous pressure
Rapid weight gain; syncope
Severe abdominal pain
Venous thrombosis
Hct >55%; WBC >25,000
Creatinine >1.6
Creat. Clearance <50 mL/min
Hyponatremia: <135 mEq/L
Hyperpotassemia: >5 mEq/L
Elevated liver enzymes
Hospitalization;
Intensive care unit
Mild Moderate Severe
13. Esteves, 13
Papanikolaou et al.,Hum Reprod. 2005; ;20:636-41;
Humaidan et al., Fertil Steril. 2010; 94: 389-400.
Psychological burden
High cycle cancellation rates
Higher risk of miscarriage
Severe Cases May Get Even Worse
Acute renal failure
Arrhythmia
Thromboembolism
Pericardial effusion
Massive hydrothorax
Arterial thrombosis
Sepsis
Adult respiratory
distress syndrome
Complications
18. Esteves, 18
Which are the Biomarkers?
●Hormonal Biomarkers: FSH, Clomiphene
citrate challenge test, Inhibin-B,
Anti-Mullerian Hormone (AMH);
●Functional Biomarkers:
Antral Follicle Count (AFC);
●Genetic Biomarkers: Single Nucleotide
Polymorphisms for FSH-R; LH/LH-R; E2-R;
AMH-R.
OHSSManagement
19. Esteves, 19 La Marca et, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097.
Dimeric glycoprotein; ~140KDa
Product of GCs of early follicles
Pre-antral and small antral (≤4-8mm)
AMH
21. Esteves, 21
AMH
Fleming et al. RBM online 2013;26:130;
Rustamov et al. Hum Reprod. 2012; 27:3085; Nelson & La Marca. RBM online 2011;23:411;
Assays have different performances
DSL and Immunotech
Beckman-Couter generation II
Fully automated ELISA (to be released)
Lack of international standardization
and EQC
Sample instability
Collection in EDTA
Storage at room temperature (up to 40% increase)
No separation of serum from blood before postage
Shortcomings and Pitfalls
22. Esteves, 22 Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700
Sum of antral follicles in both
ovaries by TVUS at early
follicular phase (D2-D4):
2-10 mm (mean diameter)
Greatest 2D-plane
AFC
Reflect No. AF at a given
time that can be
stimulated by medication
23. Esteves, 23
Lee et al., Hum Reprod 2008, 23:160–167
Cut-off: 3.36 ng/mL
Sensitivity : 90.5%
Specificity: 70% in IVF
AMH
Cut-off: 16 AF
Sensitivity: 100%
Specificity: 93%
AFC
AFC
Checa et al. Fertil Steril. 2010; 94:1105-7
Prediction of excessive response
in IUI with 75 IU/d rec-hFSH
24. Esteves, 24
Low dose step-up gonadotropin protocol
Starting dose: 37.5 – 75 IU
Adjustments according to ovarian response
Sengoku et al. Hum Reprod. 1999; 14:349-53; Cantineau et al., Cochrane Database Syst Rev.
2007; 18:CD005356., Humaidan et al., Fertil Steril. 2010; 94:389-400
Pen devices:
Precise dose delivery
Adjustments by small increments
Self-administration
OHSSManagement
25. Esteves, 25
2 RCT (n= 297)
Low dose step-up in IUI
Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356
OHSS 13% 2.7% 5.52
(95% CI: 1.85 to 16.52)
Pregnancy 31.1% 28.2% 1.15
(95% CI: 0.69 to 1.92)
OHSSManagement
26. Esteves, 26
GnRH-agonist
rather than hCG for
LH trigger
Patient frustration
Waste of time and money
Risk ovulation and
intercourse
Risk of multiple pregnancy
and late OHSS onset
Cantineau et al., Cochrane Database Syst Rev. 2007;18:CD005356;
Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96
OHSSManagement
27. Esteves, 27
LH/FSH Unload
Which and How:
Triptorelin 0.2 mg
Leuprolide acetate 1 mg
Buserelin 0.2-0.5 mg
Griesinger et al. Hum Reprod Update. 2006;12:159-68.
When:
Same criterion of hCG
14 h
20 h
14 h
48 h
20 h
4 h
GnRHa LH surge vs
natural cycle
OHSSManagement
28. Risk for OHSS markedly reduced:
3% 0% to 2.6%
Esteves, 28
GnRH-agonist vs hCG: 11 RCT – 1,055 women
Fresh
autologous
cycles (8 RCT)
Live birth Pregnancy
Moderate/
severe OHSS
OR 0.44
(0.29 - 0.68)
OR 0.45
(0.31 - 0.65)
OR 0.10,
(0.01 to 0.82)
Youssef et al. Cochrane Database Syst Rev. 2011
Chance of Pregnancy also reduced:
30% 12% to 22%
OHSSManagement
29. Esteves, 29
Aboulghar & Mansour. Hum Reprod Update 2003;9:275;
Humaidan et al. Fertil Steril 2012 ;97:529; Engmann & Benadiva Fertil Steril 2012;97:531
Modified Luteal Support in IVF:
hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses;
recLH; intense progesterone + estradiol; combined
Risk Difference for Pregnancy:
18% (Before) vs 6% (After Modified LP Support)
IVF: luteal phase insufficiency
LH suppressed due to Estrogen
Management
30. Study N Trigger
Luteal
support
Findings
Romeu
1997
761
hCG
X
1.5 mg
Leuprolide
Acetate
(2 doses
12/12h)
1,000- 2,500
IU hCG D0,
D2, D4 luteal
phase
99% ovulation rate; Similar E2
and P4 levels, miscarriage rates
Pregnancy Rates
LA (27.3%) vs hCG (17.3%;
p=0.0007); No OHSS in LA group
Romeu et al. J Assist Reprod Genet. 1997; 14:518;
Pirard et al. Hum Reprod. 2005; 20:1798; Diaz et al. J Reprod Med. 2008; 53:33.
LHTriggerwithGnRHa
inIUI
Esteves, 30
Pirard
2005
24
hCG
X
0.2 mg
Buserelin
0.1 mg
Buserelin
different
schemes
Higher P4 levels at D14 with
every day buserelin
Diaz,
2008
48
hCG
X
0.2 mg
Triptorelin
-----
Higher FSH and LH rise 24h after
triptorelin;
Higher P4 levels 48h after hCG,
albeit suboptimal
32. Esteves, 32
Youssef et al. Cochrane Database Syst Rev. 2011;16:CD001302.
IVF
20% Human
Albumin (50 mL)
6% Hydroxyethyl
starch (HES); 1L
No. Studies
(patients)
8 RCT
(n=1,660)
3 RCT
(n=487)
Severe OHSS
OR: 0.67
(95% CI: 0.45-0.99)
OR: 0.12
(0.04-0.40)
CPR
OR: 0.76
(0.48-1.21)
OR: 1.2
(0.49-2.95)
OI and IUI: Data Not Available
HowtoAvoidOHSS
Increase oncotic pressure and reverse leakage of fluid
Bind mediators of ovarian origin
33. Esteves, 33
Youssef et al., Hum Reprod Update. 2010;16:459-66;
Tang et al. Cochrane Database Syst Rev. 2012; 15;2:CD008605.
IVF
Youssef, 2010
4 RCT (n=570)
Tang, 2010
2 RCT (n=230)
OHSS
OR = 0.41
(95% CI: 0.25-0.66)
OR 0.40
(95% CI: 0.20-0.77)
Severe
OHSS
OR 0.50
(0.20-1.26)
OR 0.77
(0.24-2.45)
CPR
OR 1.07
(0.70-1.62)
OR 0.94
(0.56-.59)
Miscarriage
Rate
OR 0.31
(0.03-3.07)
OR 0.31
(0.03-3.07)
HowtoAvoidOHSS
Decrease incidence of early-onset OHSS
34. Esteves, 34
Cabergoline, Quinagolide, Bromocriptine
dopamine agonists
Basu et al. Nat Med 2001;7:569–74; Gomez et al. Endocrinology 2006; 147:5400–11.;
Soares. Fertil Steril. 2012; 97:517-22.
HowtoAvoidOHSS
In vitro studies:
Activation of dopamine receptor-2 (Dpr2) promote
internalization of VEGFR-2 (become
unreachable for VEGF);
Cabergoline in rats:
Phosphorylation of VEGFR-2 reduced by 42%;
Inhibition of VEGF production in cultured granulosa cells
exposed to hCG.
35. Esteves, 35
Most effective regimen:
0.5 mg daily for 8 days
Start on the day of hCG
administration;
Ideally a few hours before hCG is
given
Soares. Fertil Steril. 2012; 97(3):517-22.
HowtoAvoidOHSS
No major complications
36. Esteves, 36
1Minaretzis et al. J Clin Endocrinol Metab. 1995;80:430; 2Fridén & Nilsson. Acta Obstet Gynecol Scand.
2005;84:812; 3Asimakopoulos et al. Fertil Steril. 2006;86:636; 4Taylor et al. J Endocrinol. 2004;183:1;
5Lainas et al. Reprod Biol Endocrinol. 2012;10:69; 6Lainas et al. Hum Reprod. 2013; April 26.
HowtoAvoidOHSS Supress endogenous LH secretion (luteolytic effect)
Decrease vasoactive cytokines producted by corpus luteum1
Direct effect on the ovary reducing VEGF production2,3,4
Lainas et al., 20125
40 pts.; early-onset severe OHSS
Ganirelix (0.25 mg) daily from
D5-D8 after oocyte retrieval +
embryo freezing
NO HOSPITALIZATION;
Rapid resolution of OHSS
Lainas et al., 20136
22 pts.; early-onset severe OHSS
Ganirelix (0.25 mg) daily from D5-D7
after OPU + embryo transfer; 172
controls at risk of OHSS
NO HOSPITALIZATION;
Rapid resolution of OHSS;
No late-onset OHSS;
LBR: 41% (Antag.) vs 43% (controls)
37. Esteves, 37
OHSS has a dramatic psychological effect
in patients’ life; those who suffer from it
are unwilling to continue treatment.
OHSS must be PREVENTED rather than
treated.
Improving patients’ welfare starts at
identifying who are at risk for OHSS, and
continues by individualization of the
ovulation induction protocol.
KeyMessages OHSS: Management in
OI/IUI Cycles
38. Esteves, 38
Improving patients’ welfare starts at
identifying who are at risk for OHSS, and
continues by individualization of the
ovulation induction protocol.
KeyMessages
GnRH-agonists LH trigger virtually
eliminates OHSS; luteal phase support
is required.
OHSS: Management in
OI/IUI Cycles
39. Esteves, 39
Secondary prevention by albumin, HES
and carbegoline are useful but not fully
eliminate the risk.
GnRH Antagonists during luteal phase
holds promise to treat OHSS in early
stages.
KeyMessages OHSS: Management in
OI/IUI Cycles
