1. The Truth about Ovarian
Hyperstimulation Syndrome
and How to Avoid It
Sandro Esteves, M.D., Ph.D.
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, BRAZIL
ASPIRE III, June 14, Istambul, Turkey

2. Esteves, 2
Know the Numbers
Aetiopathogenesis
Clinical Aspects
What is in it for me?

3. Esteves, 3
Singleton live
birth at term
Maximize
Treatment
Beneficial Effects
Minimize Complications and
Risks
Cycle
Cancellation
Multiple
Pregnancy OHSS

4. Esteves, 4
Incidence1:
3-6% moderate OHSS
~2% severe OHSS
OHSS
1Aboulghar. Fertil Steril. 2012;97:523-6; 2Confidential Enquiry into Maternal and Child Health,
2007; 3ICMART (International Committee for Monitoring Assisted Reproductive Technologies)
: 3/100,000 cycles2
1.5 million cycles/year worldwide3
~500 deaths in the last 10 years

5. Esteves, 5
Low incidence and most cases are mild!!
Real numbers not available
Several cases unreported
OI/CC: 13.5% of mild forms
IUI: 2-8% cycle cancellation (OHSS risk)
Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; Delvigne &
Rozenberg Hum Reprod Update. 2003;9:77-96.
OHSS

6. Having
Difficulty
Conceiving
1Boivin J, et al. Hum Reprod 2007;6:1506; 2Data on file, ObGyn Research 2003, EMD Serono;
3Domar AD. Fertil Steril 2004;81:271
Treated
by
Infertility
Specialist
20% discontinue treatment before
finishing clomiphene citrate (CC)2
23% complete CC therapy and then
discontinue treatment2
45% of infertile couples never seek
medical treatment1
100
Treated by
ObGyn
55
3125-40% who come to IS for initial
consult do not initiate treatment2
60-65% who start treatment drop out
before completing treatment3
20
8

7. Esteves, 7
Fluid Shift from Intravascular to Third Space
hCG
 Vascular Permeability
Profound Intravascular
Volume Depletion and
Haemoconcentration
Massive 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; Navot et al. Fertil Steril. 1992;58:249

8. Esteves, 8
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 detected in serum,
plasma, and peritoneal fluids of women with
OHSS4

9. Esteves, 9
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

10. Esteves, 10
Delvigne & Rozenberg. Hum Reprod Update 2003, 9:77–96;
Fiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32
ClinicalAspects
Many proposed systems according to 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

11. Esteves, 11
Abdominal
distension or
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 +
Evidence of
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

12. Esteves, 12
Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Papanikolaou et al.,Hum
Reprod. 2005; ;20:636-41; Humaidan et al., Fertil Steril. 2010; 94: 389-400.
However…
Psychological burden for both patients AND doctors
Associated with high cycle cancellation rates
Higher risk of preclinical miscarriage
The TRUTH is that OHSS must be PREVENTED
rather than treated
More severe cases may progress
Acute renal failure
Arrhythmia
Thromboembolism
Pericardial effusion
Massive hydrothorax
Arterial thrombosis
Sepsis
Adult respiratory
distress syndrome
Complications

13. Esteves, 13
Identify patients at risk
Mild ovarian stimulation
Cycle cancellation
GnRH-agonist for LH trigger
HowtoAvoidOHSS
Intravenous colloids
Dopamine agonist
Antagonist in the luteal phase
Primary Prevention:
Secondary Prevention:

14. Esteves, 14
Young patients
Low body mass index
Polycystic ovaries
PCOS
Previous OHSS
Sensitive ovaries
Easily
Recognized
Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32;
Humaidan et al., Fertil Steril. 2010; 94:389-400.
HowtoAvoidOHSS
BIOMARKERS of
Ovarian Response

15. Esteves, 15
The Rotterdam Consensus
Polycystic ovary:
Ultrasound showing ≥12 follicles (2-9 mm)
AND/OR ovarian volume >10 cm3
Polycystic Ovary Syndrome: 2 out of 3
Oligo‐ and/or anovulation
Clinical and/or biochemical hyperandrogenism
Polycystic Ovary
OHSS Risk: PCOS > isolated PCOS characteristics
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.
Hum Reprod. 2004; 19:41-7.; Humaidan et al., Fertil Steril. 2010; 94:389-400
HowtoAvoidOHSS

16. Esteves, 16
Which are the Biomarkers?
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.
HowtoAvoidOHSS

17. Esteves, 17 La Marca et, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097.
What is known?
Dimeric glycoprotein; ~140KDa
Product of GCs of early follicles
Pre-antral and small antral (≤4-8mm)
Direct Biomarker of Ovarian Reserve:
AMH

18. Esteves, 18
AMH Low Inter-cycle Fluctuations (Fanchin et al, Hum Reprod 2005;20:923)
Understanding Biomarkers
Low Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006;91:4057)
ICC: 0.89; 95% IC: 0.83–0.94 ICC: 0.55; 95% IC: 0.39–0.71
Max. Variation: 17.4% Max. Variation: 108%
Can be assessed at any cycle day
with a single measurement

19. Esteves, 19 Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700
Direct Biomarker of Functional
Ovarian Reserve:
Sum of antral follicles in both ovaries by
TVUS at early follicular phase (D2-D4):
• 2-10 mm (mean diameter)
• Greatest 2D-plane
Reflect the number of antral follicles in
the ovaries at a given time that can be
stimulated by exogenous
gonadotropins
AFC
What is known?

20. Esteves, 20
Cut-off: 3.36 ng/mL
High sensitivity (90.5%)
High specificity (70%)
Lee et al., Hum Reprod 2008, 23:160–167
AFC
AFC
AMH
Cut-off: 16 AF
High sensitivity (100%)
High specificity (93%)
Prediction of excessive response
in IUI with 75 IU/d recombinant FSH
Checa et al. Fertil Steril. 2010; 94:1105-7

21. Esteves, 21
Low dose step-up protocol in pts. at risk
Starting gonadotropin 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 allowing
adjustments by small
increments and self-
administration
HowtoAvoidOHSS

22. Esteves, 22
2 RCT (n= 297)
Low dose step-up in IUI
Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356
Similar PRs and Lower Risk of OHSS by
Using Low dose Step-up in IUI
HowtoAvoidOHSS
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)

23. Esteves, 23
HowtoAvoidOHSS
GnRh-agonist
rather than hCG
for LH trigger
Drawbacks:
Patient frustration
Waste of time and money
Risk of spontaneous ovulation and patient
non-compliance with doctor´s
recommendations to avoid intercourse
Risk of multiple pregnancy and late onset OHSS
Cantineau et al., Cochrane Database Syst Rev. 2007;18:CD005356;
Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96

24. Esteves, 24
HowtoAvoidOHSS
LH/FSH Unload
What 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

25. Reduced, if not eliminated, risk for OHSS
In specific high risk patients and egg donation programs
is now the the choice.
Esteves, 25
GnRH-agonist vs hCG: 11 RCT – 1,055 women
LBR OPR
Moderate/
severe OHSS
Fresh
autologous
cycles (8 RCT)
OR 0.44
(0.29 - 0.68)
OR 0.45
(0.31 - 0.65)
OR 0.10,
(0.01 to 0.82)
Donor
recipient
cycles (3 RCT)
OR 0.90
(0.57 - 1.42)
OR 0.91
(0.59 -1.40)
OR 0.06
(0.01 - 0.31)
Youssef et al. Cochrane Database Syst Rev. 2011
HowtoAvoidOHSS

26. Esteves, 26
Aboulghar & Mansour. Hum Reprod Update 2003;9:275;
Humaidan et al. Fertil Steril 2012 ;97:529; Engmann & Benadiva Fertil Steril 2012;97:531
Challenge is to rescue luteal phase insufficiency:
Modified luteal support improves delivery rate:
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 Luteal Support)
HowtoAvoidOHSS
IVF: luteal phase is always altered
 estrogen/progesterone LH suppressed

27. 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 and D4 of
luteal phase
99% ovulation rate; No differences
in E2 and P4 levels, luteal phase
duration and miscarriage rates.
Higher Pregnancy Rates with
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, 27
Pirard,
2005
24
hCG
X
0.2 mg
Buserelin
0.1 mg
Buserelin
different
schemes
No difference in luteal phase
duration.
Higher P4 levels at D14 with
every day buserelin
Diaz,
2008
48
hCG
X
0.2 mg
Triptorelin
-----
Higher FSH and LH rise 24 h after
triptorelin.
Higher P4 levels 48h after trigger
with hCG

28. Esteves, 28
Primary Prevention:
Identify patients at risk
Mild ovarian stimulation
Cycle cancellation
GnRH-agonist for LH trigger
Secondary Prevention:
Intravenous colloids
Dopamine agonist
Antagonist in the luteal phase
HowtoAvoidOHSS

29. Esteves, 29
1Gokmen et al. Eur J Obstet Gynecol Reprod Biol. 2001;96:187; 2Konig et al. Hum Reprod.
1998;13:2421; 3Youssef et al. Cochrane Database Syst Rev. 2011;16:CD001302.
Colloid administration during oocyte retrieval for
prevention of severe OHSS in IVF/ICSI3
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 serum oncotic pressure and reverse leakage of fluids
from the intravascular space; bind mediators of ovarian origin

30. Esteves, 30
Prophylactic effect of Cabergoline versus No
Treatment in IVF/ICSI cycles
Youssef et al., Hum Reprod Update. 2010;16:459-66;
Tang et al. Cochrane Database Syst Rev. 2012; 15;2:CD008605.
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

31. Esteves, 31
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) cause
internalization of VEGFR-2 (become
unreachable for VEGF);
Cabergoline administration in rats:
Phosphorylation of VEGFR-2 reduced by 42%;
Inhibition of VEGF production in cultured granulosa cells
exposed to hCG.

32. Esteves, 32
Most effective regimen: 0.5 mg daily for 8 days
Start on the day of hCG administration; ideally a few
hours before injection is given
Soares. Fertil Steril. 2012; 97(3):517-22.
HowtoAvoidOHSS
Fair evidence demonstrate
the efficacy of Carbegoline
and other DAs to decrease
the incidence of early-onset
OHSS;
No major complications reported;

33. Esteves, 33
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 Supression of endogenous LH secretion (luteolytic effect)
Decrease vasoactive cytokines production 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)

34. Esteves, 34
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 The Truth about OHSS
and How to Avoid It

35. Esteves, 35
GnRH-agonists LH trigger virtually
eliminates OHSS; in these cases luteal
phase support will be required.
Secondary prevention by albumin/HES and
carbegoline administration are useful but
not eliminate the risk.
Antagonist GnRH antagonist administration
during the luteal phase seems promising
to prevent progression of early-onset
OHSS.
KeyMessages The Truth about OHSS
and How to Avoid It