Gonadotrpin ovarian

stimulation

Aboubakr elnashar Benha university Hospital, Egypt

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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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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 Aboubakr Elnashar

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2. Types of ovarian stimulation

Controlled

ovarian

stimulation

Super

ovulation

Induction of

ovulation

Anovulatory or ovulatory Anovulatory Patient

Multiple > one One mature

follicle

Objective

IVF IUI

Unexp inf

Example

Down regulation

Stimulation

Prevent premature

LH surge

Stimulation Stimulation Method

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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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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

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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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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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, 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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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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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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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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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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Weight reduction

Oral anti-estrogens (CC)

Obese &overweight

Normal weight &No weight loss & No ovulation

LOD GnT

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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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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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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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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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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II. Superovulation 1. Unexplained Infertility Aim:

increase cycle fecundity

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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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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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Protocol for Management (Ray et al, 2012)

6

4

2

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2. IUI Most effective when combined with IUI

PR/cycle: 17 %

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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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Cochrane, 2012

IUI with HMG:

increases CPR compared to IUI alone

increases CPR compared to TI in stimulated cycles

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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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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

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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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Company Price

(LE)

Form Mg Generic

name

Form Trade name

Abbott 20 tab 10 Dydrogesterone Oral Duphaston

Ibsa 82.5 10 amp 100 Progesteron IM Prontogest Ibsa 72 30 vag pessaries 200 Progesteron Vag or

rectal Ibsa 102 30 vag pessaries 400

Actavis 90 15 vag pessaries 200 Progesteron Vag or

rectal Cyclogest

Actavis 125 15 vag pessaries 400

Ferring 200 21 vag tab 100 Progesteron Vag Endometrin

Serono 236 jell15 tube 8 % Progesterone Vag Crinon

October 24 30 caps 100 Progesterone Vag or oral Uterocare

Pharco 18 24 caps 100 Progesterone Vag or oral Progest

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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

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.

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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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High

response

Low

response

16 4 Total AFC

4 0.5 AMH ng/ml

4 10 FSH IU/L

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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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I. Step up

Principle:

Stepwise increase in FSH

determine the FSH threshold for follicular

development

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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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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 Aboubakr Elnashar

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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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 7 5 days

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Low dose Conventional

≤6% 36% Multiple pregnancy

≤1% 6% OHSS

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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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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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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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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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> 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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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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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

10. Results

I. Ovulation >90%

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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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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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IV. Congenital anomalies. No increase

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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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III. Breast and Ovarian Cancer: No increase

IV. Local allergic reactions.

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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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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

262 lectures

1. My scientific

page on face

book: 3547

members

2. Slide share:

1228

followers

Aboubakr Elnashar