Ovulation Induction
Prof. Dr. Cem FICICIOGLU
Yeditepe University Hospital
Obstetrics and Gynecology
Foliculogenesis
60 days
1mm.
Gougeon, 1982
14 days
14 days
4-6 mm.
20 mm.
FSH Treshold
FSH
Ovulation
Atresia
Atresia
Baird DT: J Steroid Biochem 27: 15-23, 1987
Ovulation Induction
- alone,
- Prior to an IUI ( =< 2 follicles)
- Prior to an IVF (>5 follicles)
Factors
1. Demographical ( age, weight…..).
2. Causes:
• OI+Coit
• IUI
• IVF / ICSI.
Preparation
• Treatmen of the causes ( weight loses, PCO
+ Obesity )
• BMI should be 20-25 kg/m2
• General health status ( anemia )
• Folic support,
• Spermiogram/HSG
• Hormonal profile
Methods
Hormonal
Chemical
hmg
CC/ Tamoxifen Ovarian
drilling
FSH (pure)
CC+Metformin
GnRH (puls)
Bromocriptin
Rec.FSH
Aromatase
Inhibitors
Surgery
Medical
Weight loss
Ovulation Problems
Group I
Hipogonadotropik hipogonal anovulasyon ( %10 )
Group II
Normogonadotropik normoöstrojenik anovulasyonPCO (%70)
Group III
Hipergonadotropik hipoöstrojenik anovulasyon
(%10)
Group IV
Hiperprolaktinemik anovulasyon (%10)
Group III Anovulation
• FSH , LH N, E2
• Premature Ovarian Failure
• Overian Resistans
Ovulation Follow up Methods
•
•
•
•
Old
Gynecologic Exam
Vaginal smear
Basal Body Temp
Progesterone
•
•
•
•
New
Basal body temp
Serial
Ultrasonography
E2 levels
LH kit
Starting to the treatment
•
•
•
•
No ovarian cyts
Thin endometrium
ESTRADIOL <50 PG/ML
PROGESTERON <1.6 NG/ML
OI for IUI
• Aim Monofollicular development.
• Close up follow up.
• Dosage should be adjusted based on
response.
For < 4 folficular development
1.
2.
3.
4.
5.
6.
CC (clomiphene Citrate).
CC ± FSH veya ± HMG.
Aromatase Inhibitors
Gn. Standard step-up protokol.
Gn. Low dose step-up protokol.
Gn. Low dose step-up, step-down
protokol.
Cycles Cancellation
• >3 Dominant Follicles
• ESTRADİOL (E2 )>1500 PG/Ml
• DOMİNANT Follicule ( - )
HCG timing
•
•
•
•
•
Follicular diameter: 16-18mm
E2 150-250 pg/ml / per dominant foll.
Doz  2.000-10.000 IU
Early HCG -atresia, LUF
Late HCG -postmaturity
SERMs
• Binding to Er  ve Er  receptor
–
–
–
–
Clomiphene
Tamoxifen
Raloxiphene
Bazedoxifene
Clomiphene Citrate(CC)
CC
• 2 stereoisomer
– zu-clomiphene (38 %)(sis)
– en-clomiphene (62 %)(trans),
• En-clomiphene rapid degradation,
• zu-clomiphene  long half life
• Both isomere have estrogenic and
antiestrogenic activity
• Zu-clomiphene has much more
estragenic activity
• Absorbation GIS tract.
Anti-estrogenic activity
•uterus
•cervix
•vagina
CC
HYPOTALAMIC
E2 RESEPTORS
Endometrium
 FSH
and cervical (mukus)
Inhibition
OVERIAN STIMULATION
CC - Endications
• Normogonadotrophic, normoprolactinemic
anovulation
• PCOS - Anovulation
• Unexplained Infertility
• Prior IUI
•Hipotalamo-hipofizer aks sağlam olmalı!
CC
Contrendications
•E2< 40 pg/ml
•Liver dysfunction
•Pregnancy
•Overian cyts
•Age>35
•FSH>11 IU
CC-Side effects
CC- YAN ETKİLER
%
Hot flushes
Abdominal tenderness
Nausea/vomitting
Breast tenderness
Visual disturbance
Head ache
Hair loss
Dermatid, Depretion,
11
7
2
2
2
1. 5
0.3
CC - Treatment
• Day 3-5. of the menstruel cycle, 50 mg/g; 5 days
• Hiperresponders25 mg/g
• No ovulation> 50 > 100 > 150 > 200 > 250 mg/g
When HCG
• Follicular diameter 18-20mm,
• 34-40 hours laterovulation
Ovulation: USG Findings
• Disappearnece of the follicles
• Shrinkage of the follicles
• Corpus Luteum
• Fluids in the Douglas
Ovulation:Midluteal Progesterone
• >= 5 ng/ml  ovulation
>= 9 ng/ml  pregnancy?
CC-Results
• Ovulation:
%60-80
• Pregnancy:
%20-40
• Multiple Pregnancy:
%10
• Abortion
%20
:
CC
Failure
• 3 cycles, max dosage CC (150 mg)
No ovulation
• No pregnancy after successful 6
treatment cycles
CC Resistans
Alternative Treatments
• Weight loss (BMI)
• İnsülin sensitizer agents + CC
(metformin 3x500mg, 2x850mg)
•
•
•
•
•
•
Corticosteroids (Deksametazon 0.5 mg/gün) + CC (DHEAS )
Prolaktin inhibating agent + CC
Aromatase inhibitors
Gonadotrophins + CC
Gonadotrophins
IUI + CC
Insulin Sensitisizer Drugs
Hiperinsulinemia
•Folliküler gelişimin artan androjen düzeyi
ile negatif etkilenmesi
•CC cevabının bozulması
Metformin
• Glucose decreases
Hepatic production
Bowel Absorbtion
LH ve Androgens
↓
↓
↓
Normal blood glucose does not decrease with
Metformin
Metformin
Side Effects
Anorexia,Nausea, Vomitting
Diarrheae, constipation,
Vit. B12 levels ↓
Aplastic anemia, Hemolitic anemia,
Trombositopenia, Agranülositosis
Laktic asidoz
Tamoxifen
TAMOXIFEN
HIPOTALAMIC
E2 RESEPTORS
Endometrial
stimulation
 FSH
OVERIAN STIMULATION
Tamoxifen
•
•
•
•
Pregancy rates looks like CC
Spontanous abortion rate  lower than CC
No side effect to the cervical mucus
Pts with breast cancer can use this for OI.
Aromatase Inhibitors
(AI)
Aromataz
•
•
•
•
•
•
•
Aromatase, an enzyme
Ovarium,
Adipouse tissue,
Muscles,
Liver,
Breast has Aromatase enzyme
Aromatase transforms androgens to estrogens
(with FSH stimulation)
Androstenedion
Testosteron
Aromatase
Aromatase
Estron
Estradiol
ANDROGENS
AROMATASE
ESTROGENS
HYPOTALAMUS
FSH   
Overian Stimulation
Aromatase Inhibitors
• Blocks the E2 reseptors (reversible)
• No negative effects on Endometrium and
Cervical muucus.
• Multiple Pregnancy and OHSS risks are low
Aİ
Generation
Non-steroid
Steroid
(Non-reversibl)
I
Aminoglutetimid
II
Roglitimid
Fadrozol
Formestan
III
Anastrozol
Letrozol
Vorozol
Eksemestan
AI
Anastrozol
Arimidex, 28 tb,
Letrozol
Femara, 30 tb,
Dozage
Aromataz
inhibition (%)
1 mg/g
97.3
2.5 mg/g
>99.1
AI-Endications
1. CC resistans PCOS
2. Poor responders
3. Breast cancer
Aİ Contrendications
Hipersensitivity
Pregnancy
Laktation
Renal insufficiency
Aİ - Dosage
•
2.5 – 5 (1-2 ) mg / day 3-7
AI
Side effects
•
•
•
•
•
•
•
Headache (6.9%)
Nausea (6.3%),
Periferal Edema (6.2%),
Fatigue (5.2%),
Hot flushes(5.2%),
Bone and back ache(4.8%),
Rash (3.4%)
Gonadotrophin
Treatments
ART
WHO-Grup I
Hipogonadotrophic patients
WHO-Grup II
Normogonadotrophic patients
LOW-DOSE STEP-UP
112.5 IU/g
75 IU /g
1
14
21
150 IU/g
28
187.5 IU/g
35
Gonadotrophins
CONTRENDICATIONS
• Overian Failure
• Hiperprolactinemia
• No cooperation with patient
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