Gonadotrpin ovarian

stimulation

Aboubakr elnashar Benha university Hospital, Egypt

Aboubakr Elnashar

Contents

Types of anovulation

Types of ovarian stimulations

Types of Gnt

Patient selection

Indications

Contraindications

Protocols

Monitoring

Results

Complications

Conclusion

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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

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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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 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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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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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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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}. Aboubakr Elnashar

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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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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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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2. IUI Most effective when combined with IUI

PR/cycle: 17 %

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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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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

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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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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Life cycle of ovarian follicles

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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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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 Aboubakr Elnashar

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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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 (Sperof,f 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

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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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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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

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