Professor IOANNIS E. MESSINIS
MD, PhD (Aberdeen, UK), FRCOG (UK)
Department of Obs/Gynae University of Thessaly
Larissa, Greece
GONADOTROPHINS
ADMINISTRATION IN PCOS
DISCLOSURE
Nothing to disclose
• Realize the high risk of multiple
pregnancy with the conventional HMG/
HCG protocol in PCOS
• Describe the advantages of low-dose FSH protocols in PCOS
• Discuss proper monitoring in order to avoid complications (multiple
pregnancies, OHSS)
• Discuss the use of GnRH agonist triggering in IVF
Learning Objectives
At the cocnlusion of this presentation, the participant should be able to:
PCOS
• Infertility in PCOS is due to
anovulation
Figure 1.
-14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 -14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 0
20 40 60 80 100
LH (IU/I)
-14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 -14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 0
100 200 300
Estradiol (pg/ml)
-14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 -14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 0
5 10 15 20 25
Cycle days
FSH (IU/I)
-14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 -14-12-10 -8 -6 -4 -2 +2 +4 +6 +8+10+12+14 0
2 4 6 8 10 12
Cycle days
Progesterone (ng/ml)
100 80 60 40 20 0 25 20 15 10 0 5
300 200 100 0 12 10 8 6 4 2 0 14
10 6
2 -2 -6 -10
-14 -14 -10 -6 -2 2 6 10 14 LH
IU/L
FSH IU/L
E2
pg/ml
P4
ng/ml
Cycle days Cycle days
NORMAL CYCLE
Dafopoulos et al., 2009 Fertil. Steril.92,1389-94
FSH
CLASS 5 CLASS 6 CLASS 7 CLASS 8 INTERCYCLE
MIDCYCLE
10-12 16 18-20 mm
GROWTH OF THE DOMINANT FOLLICLE
Messinis, 2008; In: Infertility and Assisted Reproduction, Cambridge UP, pp. 10-24
ANOVULATION
• No follicle maturation
• No follicle rupture
• Lack of luteinization
• Low serum progesterone
• HYPOGONADOTROPHIC-
HYPOGONADISM (WHO Group I)
• PCOS (WHO Group II)
• HYPERGONADOTROPHIC HYPOGONADISM
• HYPERPROLACTINAEMIA
ANOVULATORY INFERTILITY
INFERTILITY TREATMENT IN PCOS
• Ovulation induction
• IVF/ET
AIM OF OVULATION INDUCTION
• Single follicle maturation
• Single ovulation
• Avoidance of multiple pregnancies
• Avoidance of OHSS
PCOS
Ovulation induction
• First-line
– Clomiphene citrate – Aromatase inhibitors
• Second-line
– Low-dose HMG or FSH
– Laparoscopic ovarian drilling
• Insulin sensitizers
GONADOTROPHINS IN PCOS FOR OI
As second-line treatment in:
CLOMIPHENE FAILURE or
CLOMIPHENE RESISTANCE
• Which dose of FSH?
GONADOTROPHINS IN
PCOS FOR OI
PCOS
OVULATION INDUCTION Starting FSH dose 150 IU
No. of women 41
Treatment cycles 77
No. of women conceived 27 (65.9%) Abortion rate 24.1%
Multiple pregnancy rate 36.3%
OHSS 11.7%
Wang & Gemzell, 1980 Fertil. Steril. 33, 479-86 HMG/HCG
CC failures
RESULTS OF HUMAN GONADOTROPIN
CONVENTIONAL (HMG/HCG) THERAPY (150 IU/d)
WHO GROUP I
WHO GROUP II
Patients 50 60
Treatment cycles 167 174
Ovulatory cycles 163 (98%) 165 (95%) Patients with ovulation 50 (100%) 59 (98%) Patients with pregnancy 33 (66%) 29 (48%)
Pregnancies 39 33
Term 29 24
Multiple 9 (31%) 3 (13%) Abortions 10 (26%) 9 (27%) Patients who took home
at least one baby 28 (56%)
*
22 (37%)*
P<0.05 Messinis et al., 1988; Fertil. Steril. 50, 31-3575 IU 113 IU 150 IU 225 IU FSH dose
E2
18-20 mm Follicle
HCG
LOW-DOSE FSH STEP-UP PROTOCOL
113 IU/d
75 IU/d 150
IU/d
threshold
FSH dose window
FSH levels
Days of gonadotrophin administration
* First dose reduction: when follicle >10 mm
**Second dose reduction: 3 days later
STEP-DOWN GONADOTROPHIN DOSE REGIMEN - Roterdam regimen-
Macklon & Fauser, 2002;
In: Ovulation induction, Elsevier, pp. 111-118
*
hCG**
LOW-DOSE FSH (75 IU) IN PCOS
No. (%) Range (%)
Patients
Cycles completed
Clinical pregnancies Fecundity/cycle
Uniovulatory cycles OHSS
Multiple pregnancies
717 1391
280 (40) 21-45 20% 12-24
69% 54-88 0.14 0-2.4
5.7 0-14.1
(Reviewed by
Homburg and Howles, 1999;Hum. Reprod. Update, 5, 493-499
• Patients 134 91
• Cycles 505 429
• Uniovulatory cycles 72.0% 84.0%
• Pregnancy/cycle 12.0% 11.0%
– Twins 6.7% 6.0%
– Miscarriages 35.0% 20.0%
COMPARISON BETWEEN 75 IU AND 52.5 IU STARTING DOSE OF FSH
75 IU 52.5 IU
White et al. 1996
JCEM, 81, 3821-3824
100
75
If <10mm
10mm
50
50 75
100
Step-up
Step-down
Christin-Maitre & Hugues, 2003; Hum. Reprod. 18, 1626-31
14 days
7 days
7 days
3 days
60 40 20 0 800 600 400 200 0 25 20 15 10 0
3 9 15 21 27 CYCLE DAYS LH
mIU/ml
E2 pmol/l
P4 nmol/l
OVULATION INDUCTION WITH LOW-DOSE uFSH
(Step-up)
Messinis & Milingos 1997 Hum. Reprod. Update
3, 235-53
Messinis & Milingos, 1997; Hum. Reprod. Update, 3, 235-53 ENDOGENOUS LH SURGE IN A LOW-DOSE FSH PROTOCOL
STEP-UP STEP-DOWN P
No. of cycles 85 72
Days of treatment 15.2 9.7 <0.001 Monofollicular 68.2% 32% <0.01 Multifollicular 4.7% 36% <0.001 Hyperstimulation 2.25% 11% 0.001 Ovulation rate 70.5% 51.3% <0.05 Pregnancy/cycle 18.7% 15.8%
The Recombinant FSH (Puregon) Study Group Christin-Maitre & Hugues, 2003
Hum. Reprod. 18, 1626-31
STEP-UP vs STEP-DOWN
(Low-dose rFSH)
50 IU/d 75 IU/d 100 IU/d
125 IU/d 150 IU/d
14 days 7 days 7 days 7 days 7 days
1 42
US: increments if follicle <12 mm HCG 10000 IU im
1-3 follicles ≥16 mm Calaf Alsina et al., 2003 BJOG 110, 1072-77
343 women, 945 cycles WHO group II
rFSH
Prospective, observational, non-comparative, open,
multicentre study.
1 2 3 4 5 6 60
50 40 30 20 10 0
%
Treatment cycles 16.6%
29.1%
39.9% 48.1% 50.6% 53.1%
WHO group II Low-dose rFSH
Calaf Alsina et al., 2003 BJOG 110, 1072-77
Unifollicular: 61.3%
Cancellation: 13.5%
Twins : 5.8%
Miscarriages: 9.5%
Mild OHSS : 6.8%
Cumulative pregnancy
rate
1.0 0.8 0.6 0.4 0.2 0.0
Homburg et al., 2012
Hum. Reprod. 27, 468-73 +
+
+ +
+
+ +
FSH (n=132w) CC (n=123w) + CC-censored
+ FSH-censored
Cumulative ongoing pregnancy rate
1 2 3
Cycle
CC vs Low-dose FSH (First-line)
PCOS
FSH= 288 cycles CC= 310 cycles
(n=55 women) 284 cycles
Messinis & Milingos, 1997
Hum. Reprod. Update, 3, 235-253 1 2 3 4 5 6 7 8 9 10 11 12
Treatment cycle
Clomiphene Low dose HMG 100
80 60
40 20
0 Cumulative pregnancy rate (%)
OVULATION INDUCTION IN PCOS
63%
91%
A CONSECUTIVE SERIES OF 240 NORMOGONADOTROPHIC ANOVULATORY WOMEN (CC first, followed by FSH)
0 3 6 9 12 15 18 21 24 Follow-up (months)
1 0.8
0.6 0.4 0.2 0
50%
71%
Eijkemans et al., 2003; Hum. Reprod. 18, 2357-2362 Ongoing Singleton Pregnancy Rate Resulting in Live Birth
A
120 100 80 60 40 20 0
AMH<4.7 (n=11)
AMH=4.7-10.2 (n=17)
AMH>10.2 (n=6)
Rate of good response to HMG treatment (%)
ng/ml 100%
41%
0%
Amer et al., 2013
Reprod. Biol. Endocrinol. Dec 17;11:115
AMH AND OVARIAN RESPONSE TO HMG DURING OI IN PCOS
Prospective Observational n=24 women 34 cycles
FOLLICULAR PHASE FSH
long acting
FSH
medium acting
FSH
short acting
FSH
Follicle
OVULATION INDUCTION:
Theoretic approach to the use of different FSH isoforms
Based on: Baird, 2001; Hum. Reprod. 16, 1316-18
LOD VS FSH IN PCOS
(second line in CC resistant)
Cochrane Review (9 + 16 studies)
• Clinical pregnancy rate
(OR 1.08, 95% CI 0.69-1.71)
• Live birth rate
(OR 1.04, 95% CI 0.59-1.85)
• Multiple pregnancy rate
(OR 0.13 95% CI 0.03-0.52)
• Miscarriage rate
(OR 0.81 95% CI 0.36-1.86)
Farquhar et al., 2007; 2012 Cochrane Database Syst. Rev.
(OR 0.97, 95% CI 0.59-1.59) year 2012
LOD
• In clomiphene resistant patients
• With persistently high LH
• In case of laparoscopic assessment of the pelvis
• In case they live too far away from the hospital
• Not used for non-fertility indications
INFERTILITY TREATMENT IN PCOS
• Ovulation induction
• IVF/ET
PCOS
• Increased sensitivity of the ovaries to exogenous gonadotrophins
• Increased risk for the OHSS
• No consensus regarding the most
appropriate protocol
Heijnen et al.,2006
Hum. Reprod. Update 12, 13-21
No. of oocytes retreived
No. of oocytes fertilized
IVF IN WOMEN WITH PCOS
A meta-analysis
OR for Preg/started cycle
OR for LB/started cycle Heijnen et al.,2006
Hum. Reprod. Update 12, 13-21
IVF IN WOMEN WITH PCOS
A meta-analysis
Agonists group (n=110)
Antagonists group
(n=110)
Clin. Pregn. (%) (n) 61.8 (68) 52.7 (58) 0.220 Ong. Pregn. (%) (n) 50.9 (56) 47.3 (52) 0.686 OHSS I (%) (n) 34.5 (38) 55.5 (61) 0.006 OHSS II (%) (n) 60.0 (66) 40.0 (44)
OHSS III (%) (n) 5.5 (6) 4.5 (5)
P
(Fischer’s exact test)
Lainas et al., 2010
Hum. Reprod. 25, 683-9
PCOS
GnRH Agonists vs Antagonists plus gonadotrophins
Long
Clinical Pregnancy rate
(5 RCTs) OR: 0.71 (95% CI 0.39 to 1.28)Live birth rate
(3 RCTs)OR: 0.77 (95% CI 0.27 to 2.18)
OHSS
(pooled) OR: 0.27 (95% CI 0.16 to 0.47) Tso et al., 2009
Cochrane Database Syst. Rev.
Apr 15;(2):CD006105.
PCOS
Metformin plus FSH in IVF/ICSI
No
difference
GnRH AGONISTS vs HCG
FOR TRIGGERING IN IVF/ICSI
Reduced
– OHSS (5 RCTs) OR: 0.10, 95% CI 0.01 to 0.82
Youssef et al., 2011
Cochrane Database Syst. Rev. Jan 19 Antagonist cycles
OHSS IS NOT ELIMINATED
• 6/23 women (26%) severe OHSS (5 early)
• GnRH agonist plus 1500 IU HCG
• OHSS: 0.72% (2 severe cases)
• GnRH agonist plus 1500 IU HCG (OPU)
• Two severe cases of early OHSS
– GnRH agonist without HCG
Seyhan et al, 2013
Hum Reprod 28, 2522-8
Iliodromiti et al., 2013
Hum. Reprod. 28, 2529-36
Fatemi et al., 2014
Fertil. Steril. 101, 1008-11
