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2. PCOS..Ovulation Protocols...

4. The presentations of PCOS are
heterogeneous & may change through out the
lifespan, starting from adolescence to post-
menopausal age, & may have health
impaction later in life.

6. HA
PCOM
IM

7. this has evolved four phenotypes of
PCOS

8. HA + IM+ PCOM..... classic
pcos….Metabolic
HA + IM + normal ovaries
HA + PCOM+ ovulatory cycles..non
metabolic
IM + PCOM + no HA
[ not accepted by AEPCOS society]

9. Problems in ovulation induction &
COS.
• Failure of stimulation
• Hyperstimulation
• Premature Lutenization

10. Normal
E2 (pg/ml)
FSH (IU/L)
10
High
Low
Normal
Low
1
40
10

11. Minimize amount of medication.
Ease of compliance.
No multiples (as high as 15%-20%)
No OHSS (10%-15%)
No cancellations (poor response/high
response or premature luteinization 10%-
40%)
No miscarriages (30%-50% higher)

12.  Nonstimulated – natural cycle
 Clomiphen citrate
 Enclomiphen
 Combinations
 Adjuvants..Metformin/Myoinisitol/Vit D
 Low dose gonadotropin protocols..step
up/step down
• Agonist
• Antagonist
 Trigger the ovulation
 Luteal phase support

13.  FSH threshold.
• The concentration of
FSH required to initiate
secondary recruitment.
 FSH window.
• The time frame for
which this level of FSH
needs to be maintained
for follic. recruitment
and growth. –
(mono/multifollicular
recruitment )
 LH window/ ceiling.
• Concentration of LH
essential for follicular
growth & selection of DF

14. Patients with PCOS are unlikely to benefit
from this procedure since their success in
development of a single follicle leading to
the retrieval of a single, good quality
oocyte during a spontaneous cycle
remains uncertain.

15. Ovulation is restored in 80%, but
pregnancy is achieved in 35% of patients
75% of the pregnancies occur within the
first three cycles of CC treatment
20-25% of PCOS patients remain resistant
to CC
CC is rarely associated with severe OHSS
Imani, Fertil Steril 2002
Gysler, Fertil Steril 1982
Kistner, Obstet Gynecol Surv 1965

16. • Clomiphene citrate
• Tamoxifen
• Enclomiphene
• Aromatase inhibitors

17. Two reviews from The Cochrane Library
on clinical trials investigating gonadotropin
therapy for ovulation induction in women
with clomiphene resistant PCOS,
concluded that no significant benefit could
be demonstrated from urinary FSH versus
HMG in terms of pregnancy rate, but a
significant reduction in OHSS associated
with FSH was observed. Hughes 1997, Nugent 2002

18. “Two–cell, two-gonadotrophin Concept”
 FSH works on granulosa cells-stimulating their
proliferation and growth
 FSH is active in early follicular phase thus
stimulates small follicles
 LH-acts on theca cells.. to produce androgens –
 Importance lies in the mid-to late follicular phase
stimulates large–follicle growth
 Causing atresia of small follicles- prevent OHSS
Marco Filicori

19.  Both FSH and LH are required for promoting
follicular and growth and differentiation…
FSH..principal stimulator and regulator of
antral follicular growth…
Some LH ..preantral stage..to stimulate
secretion of androgens by thecal cells…

20. The clinical pregnancy rates per cycle
started were higher with rFSH than uFSH,
although the magnitude of the observed
difference was small, 3.7%. No significant
differences were detected in the rates of
miscarriage, multiple pregnancy and
OHSS. European and Middle East Orgalutran Study
Group, Human Reprod 2001

21. During cycles without GnRH-a
suppression, either a significant LH surge
or at least marked luteinization will limit
continued gonadotropin stimulation and
thus lead to a concomitantly lower risk of
OHSS.

22. FIVNAT results showed that the use of
GnRH-a led to significantly higher
preovulatory estradiol concentrations, and
to more frequent severe hyperstimulation
(4.6% vs. 0.6% for nonGnRH-a/hMG
cycles).
FIVNAT, Contracept Fertil Sex 1989

23.  The type of GnRH agonist to be used in
patients at risk of OHSS has not been
extensively studied. It is obvious that the
short protocol should not be proposed, as the
initial flare-up effect could lead to an
excessive ovarian response.
 In the long protocol, depot formulation versus
daily injection and follicular versus luteal start
have not been compared prospectively in
patients at risk of OHSS.

24. It has been proposed that a longer period
of desensitization (30 instead of 15 days)
is of benefit by reducing androgen levels.
The longer duration of treatment did not
improve pregnancy rates but did
apparently decrease the incidence of
hyperstimulation.
Salat-Baroux, Human Reprod 1988

25. Patients receiving antagonist treatment
have lower estradiol serum levels at the
time of hCG administration, mostly
because of a lower number of follicles,
which could explain the lower incidence of
OHSS.
Ludwig M, Arch Gynecol Obstet 2000

26. There was a statistically significant
reduction in incidence of severe OHSS
with antagonist protocol. The relative risk
ratio was 0.61 (P=0.01; 95% CI 0.42 -
0.89).
In addition, interventions to prevent OHSS
(e.g. coasting, cycle cancellation) were
administered more frequently in the
agonist group (P=0.03; OR 0.44, 95% CI
0.21 - 0.93).
Al-Inany, Cochrane Database 2006

27. The GnRH-antagonist protocol involved
starting gonadotropins on day 3 of the
menstrual cycle. Transvaginal ultrasound
monitoring was commenced on day 5 of
ovarian stimulation and repeated every 2-3
days.

28. 150 IU
225 IU
3th day 7th day
USG
300 IU
USG
12th day
HCG
Antagonist (start at 6th day)

29. The starting dose for gonadotropin is
based on
• age,
• body mass index (BMI)
• existence of PCOS,
• previous history of OHSS or high response.

30. Two comparative prospective studies of
the conventional regimen, with the chronic
low-dose step-up protocol using urinary
FSH or rhFSH for ovulation induction in
PCOS patients, showed that the low-dose
approach eliminated complications of
OHSS and multiple pregnancies without
jeopardizing the incidence of pregnancy.
Homburg, Fertil Steril 1995
Hedon, Human Reprod 1998

31. 150 IU
225 IU
3th day 7th day
USG
300 IU
USG
12th day
HCG
Agonist
Mid
luteal

32. 75 IU
150 IU
3th day 7th day
USG HCG
Agonist
Mid
luteal

33. 75 IU
3th day 14th day
USG
112.5 IU
150 IU
21st day
USG

34.  The step-down protocol applies decremental doses
of gonadotropins once ovarian response is
established, but the starting dose is higher than in
the step-up approach.
 Monitoring of follicular growth is, however, more
stringent than with the step-up approach. In
addition, the long half-life of currently available
FSH preparations makes it difficult to judge the
correct reduction of dose.
 Clinical results are similar to those obtained with
the step-up approach.
van Santbrink, Human Reprod 1995

35. Agonist
3th day 6th day
USG
150 IU
300 IU
HCG
Mid
luteal

36. Unlike a step-up protocol, which
continuously rescues follicles from atresia,
a step-down protocol will allow more
follicles to undergo atresia, thus reducing
the overall number of follicles capable of
secretory activity by the time hCG is
administered.

37. An alternative method for ovulation
induction with FSH in PCOS patients is the
so-called sequential protocol, which
combines an initial step-up gonadotropin
administration followed by a step-down
regimen after follicular selection (leading
follicle > 14 mm). In a comparative study
with the standard low-dose step-up
regimen, both approaches were shown to
be safe and effective.
Hugues, Human Reprod 1996

38. For normal folliculogenesis,
LH has to be ‘just right’, neither
‘too much’ nor ‘too little’
-midfollicular phase..0.5IU/L or 1.0IU/L
decreased fertilization and clinical pregnancy rate
The Goldilocks principle:

39. More recently, Filicori et al. proposed
conducting the end of stimulation using a
treatment composed of low-dose hCG.
Low-dose hCG as a source of LH activity
was associated with FSH or was used
alone in the second part of the follicular
phase.
Filicori, Human Reprod Update 2002

40. Ovarian stimulation with daily late follicular phase administration of
low-dose human chorionic gonadotropin for in vitro fertilization:
a prospective, randomised trial Serafini, et al, Fertil Steril 2006

41. Ovarian stimulation with daily late follicular phase administration of
low-dose human chorionic gonadotropin for in vitro fertilization:
a prospective, randomised trial Serafini, et al, Fertil Steril 2006

42. Use a combination of frequent
serum estradiol measurements
and ultrasonographic
assessments of follicular growth.

43. Trigger for Ovulation…

44.  Decrease in hCG dose
• 10.000 IU vs. 5.000 IU or 3.000 IU no difference
 The use of GnRH antagonists could further
decrease the incidence of OHSS in high-risk
patients when replacing hCG by a GnRH
agonist to trigger ovulation.
 A recent prospective study found a lower
pregnancy rate in patients in whom GnRH
agonists were used to trigger ovulation.

45. There was no statistically significant
difference between rhCG vs uhCG
regarding the incidence of OHSS.
A multicenter double-blind study revealed
that new recombinant human LH can be as
effective as hCG in inducing the final
follicular maturation in IVF treatment with a
lower incidence of OHSS.
European Recombinant LH Study Group 2001
Al-Inany, Cochrane Database 2005

46. Lower the starting dose?
Change the incremental dose increase?
Shorten duration of starting dose from
14 to 7 days?

47. Treatment Regimen
50 IU starting dose; increments of 25 or 50 IU
n=158
1 8 15 22 29 35
150 IU daily
100 IU daily
125 IU daily
75 IU daily
7 days
7 days
7 days
7 days
50 IU daily
7 days
Start
day 3 of
menses
Days of treatment
1 8 15 22 29 35
250 IU daily
150 IU daily
7 days
200 IU daily
7 days
7 days
100 IU daily
7 days
50 IU daily
7 days
FSH increments: Only allowed when no follicle  12 mm
hCG: 1 follicle  18 mm
cancellation:  3 follicles  15 mm Leader et al, 2006

48. 81.3
60.3
41.3
21.8
0
25
50
75
100
ovulation rate monofollicular
cycle rate
IU increments 25
IU increments 50
n = 158
n = 107
p=0.009
p=0.009
Leader et al, 2006

49.  Only a low-dose protocol should be used for
ovulation induction in PCOS.
 Step-up more efficient and safer than step-
down.
 Small starting and incremental dose increases
recommended with no dose change for 14
days.

50. PREMATURE LUTEINIZATION

51. Peri-ovulatory progesterone plays an
indispensable role in ovulation and
luteinization
controls tissue remodelling of the ovulatory
follicle.
anti-atretic and pro-differentiative actions.
Chaffin et al HR2000.
Facilitates positive feedback response of E2 on LH.
Induces second FSH surge ensuring completion of
FSH action in the follicle.

52. FSH stimulates transcription of several
genes within the granulosa cells, leading to
the reflection of follicle differentiation

53. < Pregnancy Rate due to
• lowered oocyte quality
• premature resumption of meiosis
• impaired endometrial receptivity –
hastening of secretory changes.

54. P elevation >1- 1.5 ng/ml on or before
HCG administration during COH & the
concomitant differentiation of GC to luteal
cells.
P:E ratio>1: P ng/ml X1000 / E2 pg/ml
It is unrelated to pre-ovulatory LH rise.
Prevalence rate : 13% – 61% (Younis et al
FS 1998). Even in D/R cycles.

55. LH content of HMG. However it is seen
to occur in cycles using rFSH.
Dose of exogenous FSH administered -
PL reflects the mature GC response to
high FSH exposure. Ubaldi et al. &
Filicori et al.
Cumulative P secretion by a cohort of
maturing follicles. ( Younis 2001, Segal
et al FS 2008).

56. Gene involvement.
• A series of genes expressed differentially in
PL GCs have been identified. These genes
were vital for steroidogenesis, translation, cell
adhesion, cellular metabolism, lipid
metabolism, and apoptosis. Xingyo long et al
2009
PL could reflect low ovarian reserve.
(Younis 1998 .study in pt.’s with UI).

57. Use of GnRH analog.
• GnRH agonist.
• GnRH antagonist.
Use lower dose of gonadotrophins for
COS.
Progesterone antagonist . –
mifepristone effective in < PL, effect on
ER a concern. Escuredo et al. spain.

58. Mild stimulation
Oral contraceptive pre-treatment
Agonist vs antagonist
GnRH agonist to trigger ovulation
Metformin
Freeze embryos
IVM

59. Learn from yesterday,
live for today,
hope for tomorrow
The important thing is…not to stop
questioning
Albert Einstein

60.  The odds of OHSS were more than 2-fold higher
with treatments involving hCG than with
progesterone alone (OR 3.06, 95% CI 1.59 to
5.86).
 Comparing routes of progesterone administration,
reductions in clinical pregnancy rate with the oral
route, compared to the intramuscular or vaginal
routes, did not reach statistical significance, but
there was evidence of benefit of the intramuscular
over the vaginal route for the outcomes of ongoing
pregnancy and live birth.
Daya, Gunby, Cochrane Database 2004

61. Due to the abundance of follicles in the
ovary, PCOS patients present an excellent
clinical opportunity for the retrieval of
unstimulated immature eggs and do In
Vitro Maturation.

62.  The immature oocytes are retrieved from
antral follicles of unstimulated (or minimally
stimulated) ovaries via the transvaginal
approach.
 The oocytes are subsequently matured in
vitro in a special formulated culture medium
for 24-48 h. The mature oocytes are fertilized,
usually by intracytoplasmic sperm injection
(ICSI), and the selected embryos are
transferred to the uterus 2-3 days later.

63.  Because no expensive gonadotropin
stimulation and no extensive monitoring
scans are required, the cost of IVM treatment
is lower than that of IVF.
 The IVM treatment schedule is shorter,
causing less stress, and it is not necessary to
wait for 2 to 3 months between treatment
cycles because no stimulation is involved.
The risk of OHSS can be avoided by IVM
treatment, especially in women with
PCO/PCOS. Child, Obstet Gynecol 2002

64. ART Service Paris Montreal Taipei Helsinki Seoul Seoul
Cycles (n) 138 254 68 239 203 419
Oocytes
retrieved
12.1 11.9 22.5 8.0 15.5 16.4
Maturation
rate (%)
61.7 78.8 74.2 58.6 55.3 73.2
Fertilization
rate (%)
62 69.2 72.8 51.3 75.1 79.0
Transferred
embryo
2.4 3.4 3.8 5.0 4.3
Clinical
Pregnancy
rate(%)
24.5 24.0 33.8 26.6 21.9 32.7
Tan SL, et al. In vitro Maturation of Human Oocytes, 2007

65. Clinical pregnancy rate 35% per cycle
Implantation rate 15% per embryo
Al-Sunaidi, Fertil Steril 2007

66. Metformin has been studied and mostly
shown to restore menstrual cycles and
confirm ovulation in anywhere between 25
- 90% of cases.
A recent analysis of 13 randomized
controlled trials showed that metformin
increased the ovulation rate almost four
times compared to placebo when it was
administered in combination with
clomiphene citrate.

67. No metformin (n=159) Metformin (n=128)
Age 34.8 33
BMI 27.2 27.8
HMG ampoules 37.1 41.1
Oocytes retrieved 23.8 18.8
Embryos tranferred 2.8 3
Clinical pregnancies 37.6 30.5
Moderate and severe OHSS* 20 1
Khattab, Reprod Biomed Online, 2006

68. Metformin (n=52) Placebo (n=49)
Cancellation % 9.6 4.1
Nr of eggs 17.3 16.2
Nr of embryos transferred 2 2
Clinical preg rate % 38.5 16.3*
Live birth rate % 32.7 12.2*
Severe OHSS % 3.8 20.4*
Tang, Human Reprod, 2006
* p< 0.05

69. First described and applied by Sher et al in
1993
hCG administration postponed until the
patients serum E2 level decreases to a
safer zone.
E2 levels usually rise rapidly in the 48 h
following initiation of the coasting period,
then plateaued and began to fall 96-168 h
after the gonadotropins were stopped.

70. Cochrane review identified 13 studies of
which only one trial met the inclusion
criteria.
There was no difference in the incidence of
moderate and severe OHSS and in the
clinical pregnancy rate between the
groups.
D’Angelo et al., Cochrane Library, 2002

71. A recent review of ten studies showed that <
2% of women developed OHSS while
maintaining acceptable pregnancy rates
(36.5-63%) when coasting was continued
until serum estradiol levels fell below 3000
pg/ml.
Levinson-Tavor, Human Reprod 2003

72. Study
E2 1st day
coasting (pg/mL)
No.of days
coasting
E2 day Hcg
(pg/Ml
No.of
oocytes
Embryos
transferred
PR (%)
IR
(%)
Severe
OHSS(n)
Sher et al.1993 >6,000 >3,000 35.2 0/17
Sher et al.1995 >6,000 >3,000 21 5.4 41 0/51
Benadiva et al 1997 3,803 2 2,206 15 58.8 1/22
Tortoriello et al. 1998 4,015 3.05 2,407 15.7 4.9 44.5 16.9 3/44
Dhont et al. 1998 3,834 1.9 2,341 19.7 2.3 37.5 20 1/120
Lee et al.1998 5,167 2.8 3,667 17.3 3 max 40 4/20
Fluker et al. 1999 5,077 2 2,832 10.8 3 36.5 14.3 1/63
Egbase et al. 1999 10,055 4.9 1,410 28.3 2.7 33 3/15
Waldenstrom et al. 1999 6,292 4.3 1,870 10 51 31 1/65
Delvigne et al.2001 8,877 3 1,492 16 2 0/157
Al-Shawaf et al. 2001 4,400 3.4 1,368 11 2.1 46.5 25.5 1/50
Grochowski et al. 2001 >3,000 3.5 >3,000 32.3 18.1 2/112
Isik et al. 2001 4 3,000 18.3 3.2 50.5
Al-Shawaf et al. 2002 4,400 3.6 2,718 13.1 2.1 35.4 24.2 1/89
Ulug et al. 2002 4,563 2.9 2,613 17.5 4.2 50.7 19.0 4/207
Isaza et al. 2002 6,395 4.2 2,181 19.6 2.6 52.9 22 0/15
Chen et al. 2003 3,753 1.5 4,528 21 5 32.1 9.6 3/31
Tozer et al. 2004 4,400 4 1,433 12 1.8 33.3 20.3 0/22
Moreno et al. 2004 5,769 3.6 2,852 18.1 19 0/132
Garcia-Velasco et al. 2004 5,904 3.8 3,312 19.5 2 42.4 24.8 5/159
Ulug et al. 2004 5,365 2.7 3,113 19.8 3.5 56.8 28.8 4/233

73. Coasting < 4 days
(n=983)
Coasting >4 days
(n=240)
Age 30.2 29.9
Oocytes retrieved* 16.5 14.9
Mean no of embryos trans 2.99 3.03
Clin pregnancy rate* 52.0 35.9
Implantation rate* 26.3 18.2
Mansour, et al., Fertil Steril, 2005

74. Coasting is a good alternative that can
avoid cycle cancellation in high
responders, who have high risk of
developing severe OHSS
Even if OHSS develops after coasting both
its incidence and severity will be
diminished

75.  No one gonadotropin is superior to others for
reducing the incidence of OHSS
 Antagonist-low dose step up is the best
protocol available
 Monitoring of the E2 and USG of follicles is
crucial
 Luteal phase support with hCG increases the
incidence of OHSS.
 Progesterone intravaginally or i.m. should be
used for the patients at risk of OHSS

76. IVM is a novel method and must
be developed for better results
Coasting is an effective method
for preventing severe OHSS
No method has been developed
that will completely prevent
severe OHSS after ovarian
stimulation.

77. r FSH u FSH
Bergh, Hum Reprod 1997 5.1 1.7
Out, Hum Reprod 1995 3.2 2.0

78. OHSS is a serious, potentially life-
threatening, iatrogenic complication of
“controlled” ovarian stimulation.
To optimize the ovarian response without
provoking OHSS is the best compromise
that should be reached by an ideal
regimen of stimulation, which is
unfortunately still not consistently
achievable.

79. PCO-like ovarian ultrasound features
(more than 10 follicles) are a predictive
factor for OHSS in IVF.
Increased risk for OHSS in patients with a
LH/FSH ratio of more than 2.
The incidence of OHSS in PCOS patients
is 6%
Tibi, 1989
Delvigne, Human Reprod 1993
Brinsden, Br J Obstet Gynecol 1995

81. 81