Gonadotrpin ovarian stimulation

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

2. 262 lectures
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3. Contents
1. Types of anovulation
2. Types of ovarian stimulations
3. Types of Gnt
4. Patient selection
5. Indications
6. Contraindications
7. The starting dose
8. Protocols
9. Monitoring
10.Results
11.Complications
Conclusion
11
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4. 1. Types of 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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5. Aboubakr Elnashar

6. 2. 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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7. 3. 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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8. Preparation Trade name Route U.pr FSH LH Price Company
HMG Menogon,
Pergonal,
Humegon,
IM 95% 75 75 66 Ferring
Serono
Organon
H.P.HMG Merional
Menopur
SC <5% 75 75 66
118
Ferring
Purified FSH Metrodine IM <5% 75
Urofillotropin
<0.1 Serono
H.P.FSH Fostimon
Bravelle
Metrodine HP
SC,
IM
<5% 75
Urofillotropin
<0.001 55
70
Ibsa
Ferring
Serono
HCG Pregnyl
Profasi
IM 95% Organon
Serono
H.P.HCG Choriomon SC,
IM
<5% 70 Ibsa
I. Urinary Gonadotropins
Aboubakr Elnashar

9. 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 -
-
-
-
75,150
300,450,900
50,100
300,600
-
-
-
-
Serono
Serono
MSD
MSD
145
1200
180
--------
2. HCG Ovitrelle
Choriogonadotropin
SC - Serono 235
3. LH Luveris
lutotropin
SC - Serono
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10. CHOICE OF GONADOTROPINS
No difference in outcome between ovarian stimulation with
hMG preparations or urinary derived FSH, in studies using
the long protocol of GnRH desensitization.
(MA: Agrawal et al. 2000)
No significant clinical differences between hMG and rFSH.
(Nugent et al., Cochrane Data base Syst Rev 2000; van Wely et al, 2003)
hMG, uFSH, and r-FSH: equally effective for achieving
pregnancy in PCOS.
(Al-lnany et al.,2005)
 Rec FSH make no difference to the incidence of OHSS.
The particular FSH formulation used for ovarian stimulation
does not affect the incidence of OHSS.
(SOGC, (I)
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11. ,rFSH Vs other GN (HMG, hp-FSH, p-FSH), no
evidence of difference in LBR or OHSS
 42 trials, 9606 couples
 Further research on these comparisons is unlikely
to identify substantive differences in effectiveness or
safety
(Cochrane Database Syst Rev. 2011, Wely et al)
 Use either u or rec Gnt for ovarian stimulation
(NICE, 2013)
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12. 4. 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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13. 5. Indications
I. Induction of ovulation
1. Hypogonadotropic Hypogonadism (5-10%)
(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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14. 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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15.  2nd line tt after CC resistance/failure
(The Thessaloniki ESHRE/ASRM workshop)
{1. Lack of an oral formulation.
2. Expensive
3. Serious side effects: multiple pregnancy and OHSS
4. Close monitoring with ultrasound}.
 If AFC≤7: CC+ Gnt
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16. Aboubakr Elnashar

17. Weight reduction
Oral anti-estrogens (CC)
Obese &overweight
Normal weight &No weight loss & No ovulation
LODGnT
No ovulation after 3 cycles.
No pregnancy after 6 cycles.
No pregnancy
after 6 cycles.
No pregnancy after spontaneous,
CC, FSH ovulation
IVF
Other surgical indication
Difficult follow up
Less aggressive
No desire for
surgery
Add metformin
IGT &IR
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18. Clomiphene Citrate Resistance
Incidence:
20%
Define
No ovulation after tt 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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19. 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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20. 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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21. 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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22. II. Superovulation
1. Unexplained Infertility
Aim:
increase cycle fecundity
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23. CC Vs EM
 No better (and even inferior) LBR than EM
(14% vs 17%).
(Bhattacharya et al., 2008)
NNT: 40 for one additional pregnancy compared with
placebo
(ASRM, 2006).
No evidence that CC was more effective than no tt or
placebo for CPR or LBR
(SR by Hughes et al.;2010)
Do not offer oral ovarian stimulation agents (such as
CC, or anastrozole, letrozole).
{no increase CPR, LBR}
(NICE, 2013)
Offer IVF after 2 ys
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24.  HMG Vs CC
significantly higher CPR: 25% Vs 8%
(Karlstro¨m et al., 1993; Echochard et al., 2000 Balasch)
FSH plus Letrozole:
improved response to FSH:
lower FSH dose
higher number of mature follicles UI
(Mitwally & Casper, 2003)
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25. Protocol for Management
(Rayet al,2012)
6
4
2
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26. 2. IUI
Most effective when combined with IUI
PR/cycle: 17 %
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27. IUI with Gnt
ESHRE, 2009
PR: 12%/cycle but multiple birth rates13%.
IUI in stimulated cycles may be considered
1. while waiting for IVF or
2. when in women with patent tubes and IVF is not
affordable
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28. Cochrane, 2012
IUI with HMG:
increases CPR compared to IUI alone
increases CPR compared to TI in stimulated cycles
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29. NICE, 2013
 IUI with stimulation was better than EM in all groups
of women, but it was clear that it significantly
increased the risk of multiple pregnancies.
 IUI (with or without stimulation) should not be
routinely offered for couple with UI
 Exceptions:
 Social
 cultural or
 religious objections to IVF
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30. Monitoring:
{avoid obviously excessive stimulation}.
Risks
Multiple pregnancy: > in CC resistant anovulatory
women
Luteal support:
Not required
(Speroff et al, 2005)
{combined contributions of two or more corpora
lutea may be reliably expected to yield
supraphysiologic luteal-phase serum progesterone
concentrations}
Aboubakr Elnashar

31. LPS in IUI
vaginal progesterone: higher LBR compared with
no progesterone support
(Up todate, 2015)
(OR 2.11, 95% CI 1.213.67;three trials, 1196 cycles) (SR of RCT)
In subgroup analysis, the benefit was restricted to
Gnt stimulated cycles.
Indicated:
1. history of unexplained RM
2. luteal phase <10 days.
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32. CompanyPrice
(LE)
FormMgGeneric
name
FormTrade name
Abbott20 tab10DydrogesteroneOralDuphaston
Ibsa82.510 amp100ProgesteronIMProntogest
Ibsa7230 vag pessaries200ProgesteronVag or
rectal Ibsa10230 vag pessaries400
Actavis9015 vag pessaries200ProgesteronVag or
rectal
Cyclogest
Actavis12515 vag pessaries400
Ferring20021 vag tab100ProgesteronVagEndometrin
Serono236jell15 tube8 %ProgesteroneVagCrinon
October2430 caps100ProgesteroneVag or oralUterocare
Pharco1824 caps100ProgesteroneVag or oralProgest
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33. 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

34. 6. 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.
Aboubakr Elnashar

35. 7. 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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36. Aboubakr Elnashar

37. Aboubakr Elnashar

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

40. 8. 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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41. I. Step up
Principle:
Stepwise increase in FSH
{determine the FSH threshold for follicular
development}
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42. 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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43. 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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44. 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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45. 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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46. Low doseConventional
≤6%36%Multiple pregnancy
≤1%6%OHSS
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47. 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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48. 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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51. 9. Monitoring
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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52. 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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53.  > 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
(Speroff et al, 2005)
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54. Aboubakr Elnashar

55. 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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56. 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

57. 10. Results
I. Ovulation
>90%
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58. 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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59. 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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60. IV. Congenital anomalies.
No increase
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61. 11. Complications
I. Multiple pregnancy:
Low dose protocol: <6%
Conventional dose protocol: 36%
II. OHSS
Low dose protocol: <1%
Conventional dose protocol: 4.6%
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62. III. Breast and Ovarian Cancer: No increase
IV. Local allergic reactions.
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63. 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
Aboubakr Elnashar

64.  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
Aboubakr Elnashar

65. 262 lectures
1. My scientific
page on face
book: 3547
members
2. Slide share:
1228
followers
Aboubakr Elnashar