1. Gonadotropin Ovarian Stimulation
Aboubakr elnashar

2. Contents Types of ovarian stimulations Types of Gnt Patient selection
Indications
Contraindications
Protocols
Monitoring
Results
Complications
Conclusion

3. Types of ovarian stimulation
Induction of ovulation:
To induce monofollicular development in anovulatory patients
Superovulation:
Intentional production of more than one mature follicles

4. Controlled ovarian hyperstimulation (COH):
Regulated superovulation by turning off the patient’s own hormones (down regulation) followed by stimulation
1. Multiple follicles growth.
2. Control timing of ovulation: ova can be retrieved before they are ovulated.
3. Prevention of premature LH surge.

5. Gonadotropin Preparations
3 main preparations: FSH, LH & HCG
2 types
I. Urinary
1. HMG
Prepared from:
urine of postmenopausal women
Content:
equivalent amounts (75 IU) of FSH & LH/amp or vial
U proteins:
significant amounts, can be antigenic.
Route: IM

6. 2. Highly purified HMG: Content:
Equal amounts of FSH (75IU) & LH (75IU)
U Pr:
<5%
Route: SC

7. 3. Purified FSH Developed by:
Removing LH from u extracts (using immunoaffinity columns containing anti-hCG antibodies).
Content:
FSH (75 IU) & <1 IU LH
U protein:
95%
Route: IM

8. 4. Highly purified FSH Content: <0.001 IU LH U protein: <5%
Route: SC
minimal or no reaction at the injection site.

9. 5. Urinary HCG {structural & biologic similarity to LH} Prepared from:
human pregnancy urine & placental tissue
To simulate the LH surge: induce final follicular maturation
Dose:
5000–10,000 IU.

10. II. Recombinant 1. Rec FSH Prepared by Content: genetic engineering.
FSH isoforms
less acidic
shorter half-life
stimulate estrogen secretion as or even more efficiently.

11. Advantages: Absence of u protein More consistent supply
Less batch-to-batch variation in biologic activity.

12. 2. Rec HCG
Produced using:
techniques similar to rec FSH.
Approved:
2001 in USA
Dose:
250 µg

13. 3. Rec LH
{physicochemical, immunologic& biologic activities comparable to those of human LH}
Advantage:
An effective alterative to hCG
lower risk of OHSS.
Approved:
2000 in Europe
Dose:
15,000-30,000 IU

14. Advantages of Rec technology:
Control of source material
Purity& specific activity
Consistency of active product
Efficacy & efficiency
Safety :
1. Tailor ovarian stimulation regimens to the needs of the individual woman
2. Optimize oocyte quality& cycle fecundity.

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

16. II. Recombinant Gonadotropins
Preparation
Trade name
Route
U.pr
FSH LH
company
1. FSH
Gonal-f (follitropin)
Gonal-f FbM Pen
Puregon (follitropin)
Puregon pen
SC, IM
SC,IM
SC, Im -
75,150
300,450,900
50,100
300,600
Serono
Organon
2. HCG
Ovitrelle
Choriogonadotropin SC
3. LH
Luveris
lutotropin

17. Ready to use pre-filled pen
Rec
Consistent FSH in terms of protein content (Bassett et al, 2005).
More precise dose
More consistent ovarian response:
less treatment days
less cancelled cycles
Better embryo quality
Higher implantation rate (Hugues et al.,2002 Balasch et al, 2004)
Pen:
Easy to use
Patients prefer prefilled pen (Weiss et al, 2007)
xx/xx/xxxx
Editor: Presentation name here

18. Patient selection Basic investigations of infertility Semen analysis
HSG
Midluteal P
II. If amenorrhea &/or galactorrhea:
Workup

19. Indications Induction of ovulation 1. Hypogonadotropic Hypogonadism
(hypothalamic amenorrhea, WHO Group I)
Gnt secretion:
extremely low
Menotropin:
only effective Gnt {contains both FSH and LH}.
LH-containg Gnt if LH <3 IU/L (Speroff, 2005)
CC& related medications:
ineffective {their actions require an intact& functional hypothalamic-pituitary-ovarian axis}.

20. 2. CC resistance or failure
Resistance (No ovulation) or Failure (No pregnancy)
PCOS(WHO Group II)
Gnt: normal
LH: may be high

21. 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).

22. 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)

23. Dosage:
minimum to cause development of a single dominant follicle.
{Response can vary greatly from individual to individual& from cycle to cycle}
Monitoring:
Adjust dosage
Timing of ovulation.

24. Luteal-phase support
seldom necessary
{endogenous LH levels typically are more than sufficient to support normal luteal function}.
Indication
GnRHa used
Evidence of poor luteal function after otherwise successful ovulation induction
How:
progesterone
{higher risk of OHSS associated with hCG}

25. 1. Unexplained Infertility
II. Superovulation
1. Unexplained Infertility
Aim:
increase cycle fecundity
PR/cycle (%)
Guzik et al, 1998
1.3
No treatment 4
IUI 5 CC 8
CC with IUI
HMG 17
HMG with IUI 21
IVF/ICSI

26. 2. IUI
Most effective when combined with IUI
PR/cycle: 17 %

27. 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}

28. COH
IVF or ICSI
Aim:
induce multifollicular rather than monofollicular growth.
maintaining a sub-threshold level of Gnt during the time of follicular recruitment thus 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

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

30. Protocols Dose& duration vary among Women:
extremely sensitive to relatively low doses ( IU daily), others require greater stimulation ( IU daily).
B. wt & dose
Response cannot be predicted, even in the obese.
2. Cycles within women
The intended goal:
unifollicular ovulation or superovulation?.

31. I. Step-up: II. Step-down III. Step-up, step-down
1. Conventional=Standard
2. Low dose
3. Chronic low dose
II. Step-down
III. Step-up, step-down

32. I. Step up Principle: Stepwise increase in FSH {determine the FSH threshold for follicular development}

33. Duration of starting dose: 5 d Increased by: 75 IU/3-5 d
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)

34. If Starting dose: 150 IU/d No response® 3 FSH/day for 3 more days
Follicle > 12 mm
E2 > 400U
Continue
2 FSH/d If
No response® 3 FSH/day
for 3 more days
Endocrine Rev. 1997; 18: 71

35. 2. low-dose Stating dose: 37.5-75 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.

36. If Endocrine Rev. 1997; 18: 71 Starting dose : 37.5-75 IU/d 5 days
FSH/hMG/day
5 days
Day 7
Follicle > 12 mm
E2 > 400US
Day 3
Continue
1 FSH/d If
No response ® FSH/d
for 1 more w (max. 3 amp.)
Endocrine Rev. 1997; 18: 71

37. Duration of starting dose:14 d
3. Chronic low-dose
Starting dose: 37.5 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 reduce excessive ov stimulation
Marked dec in OHSS.

38. White et al. J Clin Endocrinol Metab 1996;81:3821–4
3 Amp.
225 iu
2 Amp.
187.5 iu
150 iu
One Amp.
112.5 iu
½ Amp.
75 iu
37.5 iu
Days 7 14 21 28 35 42 49
White et al. J Clin Endocrinol Metab 1996;81:3821–4

39. Monitoring 1- TVS: Baseline ovarian cyst:
> 30 mm: decreased fecundity (Akin and Shepard, 1993).
: postpone Gnt.

40. Daily SI on the day of HCG& for the next 2 days
b. Follicles:
1 or 2 follicles mm: HCG
Daily SI on the day of HCG& for the next 2 days
> 3 follicles > 16 mm: Stop stimulation& hCG withheld (Macklon et al, 1999).
Gnt follicles mature at mm
CC follicles mature at mm

41. C. Endometrial thickness: <6 mm: No pregnancies
9-10 mm or more: Chance of pregnancy is great
(Isaacs et al, 1996).

42. 2-E2 peak (pg/ml): <200 pregnancies are rare 500-1500 optimal
risk of OHSS is significant
>2000 pg./ml:
hCG is not given
Cyle is cancelled (Speroff et al, 2006).

43. Results
Ovulation
>90%

44. 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

45. 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

46. IV. Congenital anomalies.
No increase

47. Complications Multiple pregnancy: II. OHSS
Low dose protocol: <6%
Conventional dose protocol: 36%
II. OHSS
Low dose protocol: <1%
Conventional dose protocol: 4.5%
III. Breast & ovarian cancer: No increase
IV. Local allergic reactions.

48. Conclusion
The intended goal: unifollicular ovulation or superovulation
3 main preparations: FSH, LH & HCG & 2 types
Rec Gnt have more consistent ovarian response
Basic investigations of infertility
Indications are hypogonadotropic hypogonadism, CC failure or resistance, unexplained infertility, IUI

49. 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

50. Thank you
Dr Aboubakr Elnashar