Stimulasi Ovarium Terkendali (SOT):

Pengalaman dalam penanganan kasus

Budi Wiweko

Faculty of Medicine Universitas Indonesia

Dr. Cipto Mangunkusumo General Hospital
Jakarta
PATIENTS ENDOMETRIUM

OVARIAN STIMULATION EMBRYO TRANSFER

EMBRYO OTHERS

IVF SUCCESS
1. Berapakah jumlah oosit yang optimal untuk terjadinya
kehamilan pada program FIV ?

a. 3-5 oosit
b. 5-8 oosit
c. 10-15 oosit
d. 15-18 oosit
Fertil Steril, 2009

From oocyte to baby: a clinical evaluation of the

biological efficiency of in vitro fertilization
Pasquale Patrizio and Denny Sakkas

Objectives
To assess the real biological efficiency of assisted reproduction technology
(ART)

Result(s)
A total of 572 oocyte retrievals yielded 7213 oocytes. The total number of
transferred and frozen embryos was 2252 (utilization rate of 31.2%)

Conclusion(s):
During ART cycles, only approximately 5% of fresh oocytes produce a baby
Optimum number of oocytes for a successful first IVF
treatment cycle
Gaast van der Mark

Background Ovarian stimulation in IVF allows selection of embryos

to be replaced
Poor responder and high responder have lower chance
of pregnancy
Method Retrospective cohort study (agonist protocol)
7433 women between 18 – 45 years
Results An optimal number of oocytes was 13 oocytes

Reprod Biomed Online, 2006

Optimal number of oocyte

Bosch and Ezcurra. Reprod Biol Endocrinol, 2011

2. Jumlah oosit dan dosis rFSH dalam FIV sangat penting
karena berhubungan dengan:

a. Lonjakan LH
b. Lonjakan progesteron prematur
c. Kadar estradiol
d. Kadar hCG
 CORRELATION OF OVARIAN STIMULATION AND
PREMATURE RISING OF PROGESTERONE

Circulating progesterone levels and ongoing pregnancy

rates in controlled ovarian stimulation cycles for IVF:
analysis of over 4000 cycles

o elevated progesterone levels might be attributed to an excess

number of follicles

o increases in progesterone may reflect the mature granulosa cell

response to high FSH exposure

Bosch et al. Hum Reprod, 2010

 How was correlation between
elevated progesterone and pregnancy ?

Bosch et al. Hum Reprod, 2010

 Why progesterone is increa

Elevated progesterone level seems to be directly related to the total FSH dose
used during COS and the number of oocytes obtained

Bosch et al. Hum Reprod, 2010

3. Hal yang memengaruhi respons ovarium terhadap
stimulasi:

a. Umur
b. FAB
c. AMH
d. Indeks massa tubuh
e. Semua benar
 HOW CAN PATIENTS AND PROTOCOLS BE MATCHED ?
Matching patients with the ideal COS protocol is difficult because the
outcome of ovarian stimulation is determined by
many interacting factors

from patient’s history to genetics point of view

Bosch and Ezcurra. Reprod Biol Endocrinol, 2011

 WELCOME ………

individualized controlled ovarian stimulation

(iCOS): tailored stimulation protocols based on
biological variation

Nardo et al. Reprod Biomed Online, 2011

 PREDICTION OF rFSH STARTING DOSE
(logistic regression backward stepwise)

Variables p r
Age 0.000 0.333
AFC 0.054 -0.142
Baseline FSH 0.000 0.284
Estradiol Level 0.365 0.067
AMH Level 0.000 -0.329
n = 286

rFSH initial dose = 133 + 2.7 (Age) – 4.1 (AMH level – ng / ml)

Wiweko et al. Yasmin IVF Clinic, 2013. In preparation for publication

AMH BASED GUIDELINES FOR OVARIAN STIMULATION

pmol/ml
ng/ml

3
Antagonist

0.1
5

Scott Nelson. Fertil Steril, 2013

KASUS 1

Ny. 29 tahun

Endometriosis derajat berat (pasca laparoskopi)

AMH : 0.3 ng / ml
FAB : 8 folikel

Analisis sperma: normozoospermia

4. Protokol yang anda pilih untuk pasien tersebut di atas

a. Protokol panjang
b. Antagonis
c. Stimulasi minimal
d. Siklus alamiah
5. Dosis inisial rFSH yang akan diberikan sebesar

a. 150 IU
b. 225 IU
c. 300 IU
d. 375 IU
MRS. C, 29 YEARS OLD – SEVERE ENDOMETRIOSIS

7 oocytes
5 embryos

TOTAL DOSIS
rFSH: 2625 IU
Antagonist : 5 days

AMH 0.3 ng / ml
6. Dosis rFSH untuk stimulasi lanjutnya adalah sebesar

a. 225 IU
b. 300 IU
c. 375 IU
d. 450 IU
MRS. C, 29 YEARS OLD – SEVERE ENDOMETRIOSIS

7 oocytes
5 embryos

TOTAL DOSIS
rFSH: 2625 IU
Antagonist : 5 days

AMH 0.3 ng / ml
MRS. C, 29 YEARS OLD – SEVERE ENDOMETRIOSIS

2 EMBRYOS WERE REPLACED

Twin pregnancy
KASUS 2

Ny. 36 tahun

Azoospermia

AMH : 2.3 ng / ml
FAB : 12 folikel
7. Protokol yang anda pilih untuk pasien tersebut di atas

a. Protokol panjang
b. Antagonis
c. Stimulasi minimal
d. Siklus alamiah
8. Dosis inisial rFSH yang akan diberikan sebesar

a. 150 IU
b. 225 IU
c. 300 IU
d. 375 IU
Mrs. 36 years old - Azoospermia

11 oocytes
5 embryos

TOTAL DOSE
rFSH: 2250 IU
GnRH antagonist: 4 days
Mrs. 36 years old - Azoospermia

3 EMBRYOS WERE REPLACED

Singleton pregnancy
KASUS 3

Ny. 41 tahun

Unexplained infertility

AMH : 0.5 ng / ml
FAB : 6 folikel
MRS S, 41 YEARS OLD – POOR RESPONDER

6 oocytes
4 embryos

TOTAL DOSIS
rFSH: 3300 IU
rLH : 450 IU
Antagonist : 6 days
9. Kapan penambahan LH diperlukan ?

a. Anovulasi WHO kelas I

b. Poor responder
c. Riwayat kegagalan IVF
d. Pasien SOPK
KONSEP “ LH CEILING “
Untuk pertumbuhan folikel yang optimal diperlukan
kadar LH ≥ 1.2 IU / l dan ≤ 5 IU / l

(O’Dea et al, 2008)

Reprod Biomed Online, 2011

exogenous LH supplementation

Impact of luteinizing hormone administration on

gonadotropin-releasing hormone antagonist cycles: an
age-adjusted analysis
Ernesto Bosch, Elena Labarta, Juana Crespo, Carlos Simon, Jose Remohı, and Antonio
Pellicer

Objective:

To analyze the impact of LH administration on cycle outcome in

ovarian stimulation with GnRH antagonists

Fertil Steril, 2011

 RESULTS

The implantation rate was significantly better in those patients given

rFSH + rLH in the 36- to 39-year-old age group
The potential benefit of LH administration for older
patients could be explained by two different
mechanisms

1. The endocrine changes occurring with ovarian aging include an

increase of the serum FSH levels in the early follicular phase,
which are not accompanied by an LH increase

2. Action of LH at the follicular level that increases androgen

production may restore the follicular milieu to recover oocyte
quality, embryo quality and implantation rate

Bosch et al. Fertil Steril, 2011

a systematic review and meta-analysis

Fertility and Sterility - 2012

The use of recombinant luteinizing hormone in patients

undergoing assisted reproductive techniques with
advanced reproductive age:
Micah J Hill, Eric D Levens, Gary Levy, Mary E Ryan, John M Csokmay, Alan H De Cherney, and Brian
W Whitcomb

Objective

To evaluate the effect of recombinant LH in assisted reproduction

technology (ART) cycles in patients of advanced reproductive age
 MATERIALS AND METHODS

Literature searches were conducted to retrieve randomized

controlled trials on the use of recombinant LH plus recombinant FSH
versus the use of recombinant FSH alone in patients undergoing ART
aged 35 years and older

A total of 147 abstracts were identified, 35 full text articles were

reviewed, and from these 7 trials met full inclusion criteria

Hill et al. Fertil Steril, 2012

 RESULTS (1)

• These studies represented a total of 902 ART cycles

• Five trials used a long luteal GnRH agonist
• One trial a microdose flare
• One trial a GnRH antagonist

Hill et al. Fertil Steril, 2012

 RESULTS (2)

COMPARISON OF IMPLANTATION RATE

Humaidan et al reported a higher implantation rate in recombinant LH patients

(36.4% vs 13.3%)

Bosch et al reported a higher implantation rate in recombinant LH patients

(26.7% vs 18.6%)
 RESULTS (3)

COMPARISON OF CLINICAL PREGNANCY RATE

The fixed effect model showed an increased clinical PR in the recombinant LH

group (OR 1.37, 95% CI 1.03–1.83)
REKOMENDASI SUPLEMENTASI LH DALAM STIMULASI
OVARIUM

1. Pasien yang memiliki respon sub-optimal terhadap stimulasi

a. Tidak terdapat folikel berdiameter > 10 mm pada hari ke – 6
stimulasi
b. Kadar estradiol < 180 pg / ml pada hari ke – 6 stimulasi
c. Pertumbuhan folikel < 2 mm / 3 hari

2. Pasien berumur > 35 tahun

Reprod Biomed Online, 2011

MRS S, 41 YEARS OLD – POOR RESPONDER

4 EMBRYOS WERE REPLACED

Singleton pregnancy
 PENGALAMAN PENANGANAN KASUS

NO KASUS KELUHAN HORMON USG DIAGNOSIS

4 Ny. 31 tahun Amenorea primer FSH 1.2 Uterus AF < normal Amenorea
Infertilitas primer 9 LH 0.5 Kedua ovaria < normal primer suspek
M2-P2 tahun E2 21 FAB kecil-kecil kelainan
46, XX sentral
Uji P negatif AMH 2.8

5 Ny. 31 tahun Amenorea sekunder FSH 4 Uterus AF 5 cm Amenorea

Infertilitas primer 4 LH 2.86 Kedua ovaria < normal sekunder
tahun E2 15 FAB 8 folikel suspek
kelainan
Uji P negatif AMH 1.91 sentral

6 Ny. 40 tahun Infertilitas primer 13 AMH 2.3 Uterus normal Infertilitas

tahun FAB 10 folikel primer 13
Riwayat partus tahun
imaturus (IVF I)
Poor
responder ?

Wiweko. Klinik Yasmin, 2012

 hari hCG

LH = 0.4
Estradiol = 1998 pg / ml
Progesteron = 1.0 ng / ml

TOTAL DOSIS
rFSH: 1650 IU
rLH : 825 IU
 hari hCG

LH = 4.9
Estradiol = 2278 pg / ml
Progesteron = 1.0

TOTAL DOSIS
rFSH : 2100 IU
rLH: 750 U
hari hCG
LH = 3.13
Estradiol = 2996 pg / ml
Progesteron = 1.1 ng/ml

TOTAL DOSIS
rFSH : 4625 IU
rLH : 450 IU
Antagonis GnRH (6 hari)
 BAGAIMANA LUARAN – NYA ?
NO DOSIS LH DIBERIKAN Hari hCG OPU + ET PASCA ET

4 rFSH 1650 11 hari LH 0.4 Oosit 14 Kehamilan

rLH 825 hari ke-1 Estradiol 1998 ET 4 embrio tunggal
tanpa antagonis Progesteron 1.0
GnRH 5 embrio dibekukan Sudah melahirkan
Amenorea (+)

5 rFSH 2100 10 hari LH 4.9 Oosit 16 hCG 1104

rLH 750 hari ke-1 Estradiol 2278
tanpa antagonis Progesteron 1.0 ET 2 embrio Kehamilan gemelli
GnRH (expanded
blastocyst)

4 embrio dibekukan

6 rFSH 4625 6 hari LH 3.13 Oosit 14 hCG 399

rLH 450 hari ke-7 Estradiol 2996 ET 3 embrio
antagonis GnRH hari Progesteron 1.1
ke-7 4 embrio dibekukan

Wiweko. Klinik Yasmin, 2012

Kasus 7

NY. ROS, 30 THN

INFERTILITAS PRIMER 3 THN

Jumlah total / ml : 23.6 x 106

Motilitas sperma : 42%
Morfologi normal : 25%

Oklusi tuba bilateral

FSH
LH 4.2
E2
PRL
P4
√ 2981

0,4
13 18
USG Kanan
12
USG Kiri 13 19
12 20
Endo 10 13
siklus haid 1 2 3 4 5 6 7 8 9 10
Tgl 28 29 30 31 1 2 3 4 5 6
rFSH 200
rLH
Elonva 150 x
Femara
GnRHa
GnRH ant 0.25 0.25 0.25 0.25
hCG 20:00

OPU 8:00

ET

Ovarium
kanan Ovarium kiri
Jml
folikel 9 8 Lama stimulasi : 8 hari
Oosit 8 8 Tambahan rFSH : 200 IU
Jml
oosit: 16

AMH
BB
6.3
50 kg √
 Hari Keempat, 10-2-2014

Embryo 2 Embryo 4 Embryo 5 Embryo 6

Ditransfer

Embryo 7 Embryo 8 Embryo 9 Embryo 14 Embryo 15

Beta-HCG : 650,60 HAMIL

Progesteron : >60,00 triplet
 CORRIFOLLITROPIN ALFA GROUP

No Variable Elonva 100 (n=4) Elonva 150 (n=45)

1 Age 29.5 (27-37) 34 (21-44)

2 Body Weight (kg) 47.5 (47-53) 60 (40-76.6)

3 Serum AMH 1.75 (0.84-2.66) 2.88 (0.57-17)

4 Follicles
• stimulation Day 8 4 (3-6) 4 (3-4)
• day of HCG 5 (4-7) 4 (3-6)
5 Additional rFSH 675 (650-850) 525 (150-3000)

6 Mature oocytes 12 (6-15) 10 (1-25)

7 Fertilization rates (%) 42 (33-67) 61 (32-100)

8 Cleavage rates (%) 100 100

9 Blastocyst rate (%) N/A 18 (11-44)

10 Biochemical pregnancy 2 (66.7%, n=3) 26 (70.3%, n=37)

11 Clinical pregnancy 2 (66.7%, n=3) 15 (40.5%, n=37)

12 Day of COS 10 (10-11) 9 (7-19)

 Kasus 8

NY. HLS, 29 THN

AMENORE PRIMER
HIPOGONADOTROPIN-HIPOGONADISME
(WHO KELAS 1)

Tahun 2012
FSH : 0.9
LH : 0.77
E2 : < 37
PRL : 0.23
FSH
LH 0,747 0,8
E2 1150 3010
PRL
P4 0,7
USG 12 14 20
Kanan 13 15 20
11 15 20
USG Kiri
11 14 20
Endo 8 9 12
siklus
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
haid
Tgl 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
rFSH 150 150 150 150 150 225 225 300 300 300 300 300
rLH 75 75 75 75 75 75 75 75 75 150 150 150
CC
Femara
GnRHa
GnRH ant
HCG 20.00
OPU 08.30
ET

Ovarium Ovariu
kanan m kiri
Jml folikel 20 22
Oosit
Jml oosit: 39
Lama stimulasi : 12 hari
AMH 0.8 Tambahan rFSH : 2700 IU

BB: 50 kg
 RIWAYAT IVF
Amenore Primer Cyclo progynova Sperma:
Konsentrasi : 75,7
Motilitas : 59%
Morfologi : 29%
FIV
FSH : 0,7
LH : 0,38
E2 : < 43,6
OPU : 39 Oosit PRL : 0,20
(12 Blastokista)
ET : Tunda  OHSS
12 Blastokista 
Frozen

2012
 2013 2014

FET I (+)  hamil (+) FET III (+)  hamil (+)

 miscarriage

Beta hCG : 107,84 Beta hCG : 527,9

P4 : 7,12 P4 : 8,58

FET II (+)  hamil (-)  re-frozen embryos

Beta hCG : < 0,100

P4 : 7,3
 BEFORE FREEZING

Embryo 6 Embryo 16 Embryo 18 Embryo 19

RE-FROZEN
 AFTER THAWING (2014)

ET : 2

Embryo 6 Embryo 16 Embryo 18 Embryo 19

 CP (+)  2 GS
GS1 : FE (-), YS (+)
GS2 : FE (+), DJJ (+)
1. Jumlah oosit dan dosis rFSH dapat mempengaruhi terjadinya
lonjakan progesteron prematur

2. AMH dapat digunakan sebagai salah satu parameter untuk

menentukan pemilihan protokol FIV

3. Suplementasi LH meningkatkan kehamilan terutama pada pasien

berusia > 35 tahun

4. Corifollitropin alfa dapat dipertimbangkan sebagai pilihan dalam

stimulasi ovarium terkendali
 WELCOME TO
THE 6th CONGRESS OF ASPIRE

Jakarta 8th-10th, 2016