Ovarian Stimulation in IUI- Overview

Dr. Jyoti BhaskarMD MRCOG

Director Lifecare IVF

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Rationale for COH in IUI

• Increasing the number of eggs available for fertilisation

• Overcoming subtle defects in ovulatory function and luteal phase.

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Aim of COH

1. Recruiting multiple follicles

2. Control timing of ovulation

3. Prevention of premature LH surge

4. To time the insemination

5. Increase the pregnancy rate

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Optimum Ovarian Stimulationfor IUI

2 – 3 follicles with Ø 18 – 20 mm.

Endometrium 8 mm thick & trilaminar.

IUI between Cycle D13 and D16, 36-40 hrs. from HCG inj.

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Classification

WHO• I - Hypothalamic pituitary failure

(Hypogonadotrophic hypogonadism)

Kallman’s, Sheehan’s, anorexia• II - Hypothalamic pituitary dysfunction

(PCOS)• III – Ovulatory Failure – Hypergonadotrophic

hypogonadism, Turner’s, autoimmune, mumps, RT, CT

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Drugs for Ovarian Stimulation

• Clomiphene Citrate, Tamoxifen• Gonadotrophins:

• HMG• Highly purified urinary FSH • Recombinant. FSH

• GnRH Agonist/ Antagonist GnRH Agonist/ Antagonist

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CLOMIPHENE CITRATE

• Most widely

• Simple to use, Minimal side effects, Cost effective

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CLOMIPHENE CITRATE ( SERM)CLOMIPHENE CITRATE ( SERM)

HYPOTHALAMUS ER HYPOTHALAMUS ER

BindsBinds

GnRHGnRH

Pituitary Pituitary

FSHFSH

OVARY OVARY

FolliculogenesisFolliculogenesis

Blocks ERBlocks ER

CervixCervix

EndometriumEndometrium

VaginaVagina

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DOSAGE

• Single dose -- together

• Monitor Cycle with USG

• If ovulation confirmed – maintain same dose

• Max to 150 mg

Starting Dose 100mg day 2 onwards for 5 daysStarting Dose 100mg day 2 onwards for 5 days

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CC CHECK

Evaluation of the patient on Day 2

• Previous cycles

• TVS – ET , AFC and cysts

• Review reports of FSH, LH if available

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CC FAILURE ( 40%)No Pregnancy 3 CYCLES OF CC

WITH OVULATION AND TIMED INTERCOURSE

CC FAILURE ( 40%)No Pregnancy 3 CYCLES OF CC

WITH OVULATION AND TIMED INTERCOURSE

2 CYCLES OF CC WITH IUI2 CYCLES OF CC WITH IUI

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CC RESISTANCE (20%)

3 CYCLES OF CC

NO OVULATION

CC RESISTANCE (20%)

3 CYCLES OF CC

NO OVULATION

CC + GONADOTROPHINS

CC + GONADOTROPHINS GONADOTROPHINSGONADOTROPHINS

COST , PT’S CHOICE

COUNSELLING

COST , PT’S CHOICE

COUNSELLING

Wt loss, extended CC, adjuvants – metformin, dexamethasone

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Antioestrogenic Effect

• Thin Endometrium

• Poor cervical Mucus

Start early in cycle – Day 2 or Day 1Add oestradiol valearate from day 8/9

Use all gonadotrophin cycle

Start early in cycle – Day 2 or Day 1Add oestradiol valearate from day 8/9

Use all gonadotrophin cycle

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Gonadotrophins - Indications

CC Resistance

CC Failure

WHO 1

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• HMG• Highly purified Urinary HMG/FSH • Recombinant. FSH

Choice of Gonadotrophins

Day 2 LH/FSHDay 2 LH/FSH

FSHFSH

LH

PCOS

LH

PCOS

FSH

WHO group1

FSH

WHO group1

HMGHMG

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DOSE

• BMI

• Ovarian reserve

• Age

• Cause of Infertility

• Dose needed in previous cycle

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Complications

Multifetal pregnancy

• OHSS - Life threatening

MonitoringExperience

Strict protocols

MonitoringExperience

Strict protocols

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1. CC only with TI or IUI

2. CC ± FSH or ± HMG with IUI

3. Gonadotrophin only

n Conventional regime

n Gn. Low dose step-up protocol

n Gn. step-down protocol

4. Gonadotrophin with GnRH antag

Protocols

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DAYS OF CYCLE

TVS – ET AND AFC

CC100 MG DAILY

Day 2-6

TVS – FOLLICLE SIZE, ET

IF ET< 5MM OV 2MG BD DAILY

TVS – FOLLICLE , ET , CERVICAL MUCUS STUDY, POST COITAL TEST

FOLLICLE >20MM -- LH SURGE

+ VE -VE

Inj HCG 5000 U i/m

Timed Intercourse

8pm stat

IUI

36 hrs later at 8am at Lifecare24hrs later at 8am

Sexual relation at same night and for 2 days

Luteal support – ETV ES/ Susten vaginally at night

Serum Progesterone 7 days after IUI/Ovulation

CC ONLY PROTOCOL -- +/- IUI

B LONG F ONCE DAILY ALL THROUGH OUT THE CYCLE

UPT 18 days after IUI/Ovulation

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Unripe follicle

Ripening follicle

Ovulation Corpus luteum

Regression of Corpus luteum

Clomiphene 100 mg day2

for 5 days

Gonadotrophin stimulation

HCG Leading follicle > 18mm

Oocyte mature

38 hrs

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Days 7 14 21 28

hCG

150 IU 112.5 IU 75 IU hCG

Foll. 10 mm

75-150 U daily

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hCG

Foll. 16mm

Gonadotrophin Regimens

37.5 IU 75 IU 112.5 IU 150 IU

Chronic Low dose Step up regimen

Step down

Conventional Regime

2 6

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Gonadotrophins with Antagonists

15-20% cycles with Gonadotrophins have premature LH surge

15-20% cycles with Gonadotrophins have premature LH surge

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Advantages of Antagonist Protocol

• Helps avoid IUI at weekends

• Prevents premature surge

• Compared to agonist – simple and inexpensive

• Lower rates of OHSS

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Anti-oestrogens

Cost effective but less effective when compared to gonadotrophins.

Do not prevent multiple pregnancies

Have anti-oestrogenic effect on the endometrium

Gonadotrophins

Most effective drugs for IUILow dose protocols (50 to 75 IU per day) are advised

Pregnancy rates do not seem to differ significantly from pregnancy rates with high dose regimens (> 75 IU per day) whereas the changes to encounter negative effects from ovarian stimulation, such as the risk of multiples and the risk of OHSS might be higher with high dose protocols.

24The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJThe Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ

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GnRH-agonists There seems to be no role in IUI programsIncrease costs Increase multiples without increasing the probability of conception

Urinary gonadotrophins versus Recombinant productsThere is no significant difference

GnRH-antagonistsWhether or not are going to play a role in mild ovarian hyperstimulation/IUI programs needs to be determined in future trials.

LetrozoleThere is no convincing evidence that Letrozole is superior to clomiphene citrate and therefore the cost should be taken into account when using anti-oestrogens.

The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJThe Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ

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Ovarian stimulation protocols(anti-oestrogens, gonadotrophins with and without GnRH

agonists/antagonists)for intrauterine insemination (IUI) in women with subfertility

(Review) The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ

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Gonadotrophins might be the most effective drugs with IUI

Low dose protocols are advised

No studies using CC + gonadotrophins

Gonadotrophins might be the most effective drugs with IUI

Low dose protocols are advised

No studies using CC + gonadotrophins

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• There is evidence that IUI with OH increases the live birth rate compared to IUI alone.

• The likelihood of pregnancy was also increased for treatment with IUI compared to TI both in stimulated cycles.

• There is insufficient data on multiple pregnancies and other adverse events for treatment with OH.

• Therefore, couples should be fully informed about the risks of IUI and OH as well as alternative treatment options.

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Conclusion

Ovarian Stimulation protocol • Simple

• Cost Effective

• Minimal side effects

• Best success rates

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Conclusion

• Choice depends on doctors expertise and patient selection and choice

• Gonadotrophin only protocol offers the best success rate

TIME TO MOVE ON TO TOTAL GONADOTROPHIN CYCLE

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Thank you