1. Gonadotrpin ovarian
stimulation
Aboubakr elnashar
Benha university Hospital, EgyptAboubakr Elnashar

2. Contents
Types of anovulation
Types of ovarian stimulations
Types of Gnt
Patient selection
Indications
Contraindications
Protocols
Monitoring
Results
Complications
Conclusion
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3. Anovulation
% Type Hormonal profile
5-10%
WHO type I
(Hypogonadotropic
Hypoestrogenic)
E2
FSH
75-80%
WHO type II
Normogenadotrophic
Normoestrogenic
Normal E2
Normal FSH
10-20%
WHO type III
(Hypergonadotropic
Hypoestrogenic)
E2
FSH
5-10%
WHO type IV
(Hyperprolactinemia) prolactin
WHO Scientific group, Geneva 1976, Report 514, Rowe et al, 1993
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4. Types of ovarian stimulation
Controlled
ovarian
stimulation
Super
ovulation
Induction of
ovulation
Anovulatory or ovulatoryAnovulatoryPatient
Multiple> oneOne mature
follicle
Objective
IVFIUI
Unexp inf
Example
Down regulation
Stimulation
Prevent premature
LH surge
StimulationStimulationMethod
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5. Gonadotropin Preparations
• 3 main preparations: FSH, LH & HCG
• 2 types
I. Urinary
1. HMG
2. Highly purified HMG
3. Purified FSH
4. Highly purified FSH
5. Urinary HCG
II. Recombinant
1. Rec FSH
2. Rec HCG
3. Rec LH
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6. Aboubakr Elnashar

7. Aboubakr Elnashar

8. Aboubakr Elnashar

9. Preparation Trade name Route U.pr FSH LH Price Company
HMG Pergonal,
Humegon,
Menogon,
Merional
IM 95% 75 75 Serono
Organon
Ibsa
H.P.HMG Menopur SC <5% 75 75 Ferring
Purified
FSH
Metrodine IM <5% 75
Urofillotropin
<0.1 Serono
H.P.FSH Fostimon
Metrodine HP
Bravelle
SC,
IM
<5% 75
Urofillotropin
<0.001 Ibsa
Serono
Ferring
HCG Pregnyl
Profasi
IM 95% Organon
Serono
H.P.HCG Choriomon SC,
IM
<5% Ibsa
I. Urinary Gonadotropins
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10. II. Recombinant Gonadotropins
Preparation Trade name Route U.pr FSH LH company Price
1. FSH Gonal-f (follitropin)
Gonal-f FbM Pen
Puregon (follitropin)
Puregon pen
SC, IM
SC, IM
SC,IM
SC, Im
-
-
-
-
75,150
300,450,900
50,100
300,600
-
-
-
-
Serono
Serono
MSD
MSD
145
1200
180
--------
2. HCG Ovitrelle
Choriogonadotropin
SC - Serono
3. LH Luveris
lutotropin
SC - Serono
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11. Patient selection
I. Basic investigations of infertility
1. Semen analysis
2. HSG
3. Midluteal P
II. If amenorrhea &/or galactorrhea:
Workup
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12. Indications
I. Induction of ovulation
1. Hypogonadotropic Hypogonadism
(hypothalamic amenorrhea, WHO Group I)
Gnt secretion:
extremely low
HMG:
only effective Gnt {contains both FSH and LH}.
LH-containg Gnt if LH <3 IU/L (Speroff, 2009)
CC& related medications:
ineffective {their actions require an intact& functional
hypothalamic-pituitary-ovarian axis}.
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13. 2. CC resistance or failure
Resistance (No ovulation) or
Failure (No pregnancy)
PCOS(WHO Group II)
Gnt: normal
LH: may be high
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14. Clomiphene Citrate Resistantce
Incidence:
20%
Define
No ovulation after treatment with CC,
{100 mg, for 5 days in 3 cycles} (Coelingh
Bennink, 1998).
Causes:
Hyperandrogenic
Obese
Severe insulin resistance
(Murakawa et al.,1999; Speroff et al., 1999).
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15. Clomiphene citrate failure:
Define:
No pregnancy despite of ovulation with CC
Causes:
long half-life& peripheral anti-estrogenic effects on
endometrium& cervical mucus.
low fertilization rate
variable implantation rate
deficient corpus luteum function (Speroff et al., 2005)
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16. Dosage:
Minimum: single dominant follicle.
{Response can vary greatly from individual to
individual& from cycle to cycle}
Monitoring:
Adjust dosage
Timing of ovulation.
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17. Luteal-phase support
seldom necessary
{endogenous LH levels typically are more than
sufficient to support normal luteal function}.
Indication
1. GnRHa used
2. Evidence of poor luteal function after otherwise
successful ovulation induction
 How:
progesterone
{higher risk of OHSS associated with hCG}
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18. II. Superovulation
1. Unexplained Infertility
Aim:
increase cycle fecundity
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19. 2. IUI
Most effective when combined with IUI
PR/cycle: 17 %
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20. Monitoring:
{avoid obviously excessive stimulation}.
Risks
Multiple pregnancy: > in clomiphene-resistant anovulatory
women
Luteal support:
Not required {combined contributions of two or more corpora
lutea may be reliably expected to yield supraphysiologic luteal-
phase serum progesterone concentrations}
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21. III. COS
IVF or ICSI
Aim:
induce multifollicular growth.
maintaining a subthreshold level of Gnt during the
time of follicular recruitment: overriding the process of
selection of a single dominant follicle.
How:
GnRHa, or antagonist to block endogenous LH
production& LH surges.
Gnt
HCG
When an appropriate follicular size is observed: final
maturation of the follicles Aboubakr Elnashar

22. Contraindications
Rare:
1. Hypersensitivity to Gnt or to any of
the excipients.
2. Ovarian, uterine, or breast cancers.
3. Tumors of the hypothalamus&
pituitary gland
4. Ovarian enlargement or cyst not
due to PCOS
5. Pregnancy& lactation.
6. Gynecological hemorrhages of
unknown origin.
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23. Aboubakr Elnashar

24. Aboubakr Elnashar

25. The starting dose of Gnt
Depend on:
1. The intended goal:
unifollicular ovulation or superovulation
2. Age
3. BMI
4. PCOS
5. Ovarian reserve: baseline FSH, ACF, AMH
6. Previous response.
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26. Life cycle of ovarian follicles
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27. Aboubakr Elnashar

28. High
response
Low
response
164Total AFC
40.5AMH ng/ml
410FSH IU/L
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29. Aboubakr Elnashar

30. Aboubakr Elnashar

31. Protocols
I. Step-up:
1. Conventional=Standard
2. Low dose
3. Chronic low dose
II. Step-down
III. Step-up, step-down
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32. I. Step up
Principle:
Stepwise increase in FSH {determine the FSH threshold
for follicular development}
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33. 1. Conventional:
Starting dose: 150 IU/d:
Duration of starting dose: 5 d
Increased by: 75 IU/3-5 d
Excessive follicle development
Increased OHSS
(Thompson and Hansen, 1970; Dor et al., 1980; Wang and Gemzell, 1980).
No longer recommended
(Buvat et al., 1989; Brzyski et al., 1995)
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34. Starting dose: 150 IU/d
2 FSH/hMG/day
Day 3Day 3 Day 7Day 75 days5 days
If
Follicle > 12 mm
E2 > 400U
Continue
2 FSH/d
No response® 3 FSH/day
for 3 more days
Endocrine Rev. 1997; 18: 71
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35. 2. low-dose
•Stating dose: 75 IU/d
(White et al., 1996; Hayden et al., 1999; Balasch et al., 2000; Calaf et
al., 2003).
•Duration of starting dose: 5-7 d
-No follicle development: increase the dose by
100%
-Follicle growth: maintain same dose until
follicular selection is achieved.
-Mono-ovulation: 69%
- MP: 5.7%
- OHSS: 0.14%
(Homburg & Howles, 1999. Hum. Reprod. Update 5:493-499).
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36. Starting dose:75 IU/d
If
mm12>Follicle
E2 > 400
Continue
1 FSH/d
No response 150 FSH/d
for 1 more w (max. 3 amp.)
Endocrine Rev. 1997; 18: 71
75 FSH/hMG/day
Day 3 Day 75 days
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37. Low doseConventional
≤6%36%Multiple pregnancy
≤1%6%OHSS
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38. 3. Chronic low-dose
•Starting dose: 37.5-75 IU
•Duration of starting dose:14 d
•The weekly dose increment: reduced from 100% to 50% or
37.5 IU
(Seibel et al., 1984; Polson et al., 1987; Sagle et al., 1991; Dale et al., 1993).
:Markedly ↓excessive ov stimulation
Marked ↓OHSS.
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39. 0 14 21 28 35
75 iu
112.5 iu
150 iu
187.5 iu
225 iu
Days
7
37.5 iu
½ Amp.
One Amp.
42 49
2 Amp.
3 Amp.
White et al. J Clin Endocrinol Metab 1996;81:3821–4
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40. Monitoring in superovulation
1- TVS:
Baseline D2 or 3 of the cycle
 ovarian cyst:
> 30 mm: decreased fecundity (Akin and Shepard, 1993).
: postpone Gnt.
AFC:
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41. Serial
D5-7 of stimulation
Repeat /2-3 d depending on the size of
leading follicle, until it is 18 mm
a. Follicles:
number & size
Documentation of all follicles >10 mm {predict the risk of
multiple pregnancies}.
1 or 2 follicles 18-20 mm: HCG
Daily SI on the day of HCG& for the next 2 days
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42.  > 3 follicles > 16 mm:
(Macklon et al, 1999).
>4 follicles ≥ 14 mm
(Kamrava et al., 1982; Hugues et al., 2006).
Stop stimulation& hCG withheld
 Gnt follicles mature at 15-18 mm
CC follicles mature at 18-20 mm
(Sperof,f 2005)
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43. Aboubakr Elnashar

44. b. Endometrial thickness:
<6 mm: No pregnancies
9-10 mm or more: The chance of pregnancy is
great
(Isaacs et al, 1996).
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45. 2-E2 peak (pg/ml):
<200
pregnancies are rare
500-1500
optimal
1500-2000
risk of OHSS is significant
>2000 pg./ml:
hCG is not given
Cyle is cancelled
(Speroff et al, 2006). Aboubakr Elnashar

46. Results
I. Ovulation
>90%
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47. II. Pregnancy
Low:
1. hyperandrogenic chronic anovulation group
2. Above 35 y
CC resistant
anovulatory
Hypogonadotropic
hypogonadism
5-15%25%Cycle fecundity
30-60%90%Cumulative PR after up to 6 cycles
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48. III. Miscarriage
20-25%
moderately higher than is generally (15%).
1. advanced maternal age
2. obesity
Low in
hypogonadotropic hypogonadism
Higher in
clomiphene-resistant anovulatory women
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49. IV. Congenital anomalies.
No increase
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50. Complications
I. Multiple pregnancy:
Low dose protocol: <6%
Conventional dose protocol: 36%
II. OHSS
Low dose protocol: <1%
Conventional dose protocol: 4.6%
III. Breast and Ovarian Cancer: No increase
IV. Local allergic reactions.
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51. Conclusion
The intended goal: unifollicular ovulation or
superovulation
 3 main preparations: FSH, LH & HCG & 2
types
 Basic investigations of infertility
 Indications are hypogonadotropic
hypogonadism, CC failure or resistance,
unexplained infertility, IUI
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52.  Contraindications are rare
 Step up chronic low dose protocol is
recommended in PCOS
 US monitoring is mandatory
 Ovulation 90%, Pregnancy 30-90%,
miscarriage 20%
 Complications are OHSS &multiple
pregnancy
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53. Thank you
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