Ovarian Stimulation

Back to Basics

Dr Parul Sehgal

Incharge IVF,

Maharaja Agrasen Infertility and ART centre

Maharja Agrasen Hospital, Punjabi Bagh, New Delhi-26

Road to Infertility can be Tough and Tiring

Treatment may involve advanced infrastructure

delicate hormone balancingcareful handling of gametes

But in the end once inside the mothers body

nature take over

END RESULT IS TRULY A NATURES GIFT

1+1

1+2

INFERTILITY FACTS

• 1 in 7 couple suffer from infertility• For past few decades more and more nulligravid

females are now infertile• Time is critically important factors for couples as AGE is

the single most important prognosticator for success• Chance of spontaneous pregnancy in a healthy couple is

30 % in a cycle.• In subfertile couple during the three years after first

infertility consultation , chance of spontaneous conception followed by live birth is 25-40%, so in a cycle, fecundity rate is 0.7 – 1%. This drops further by 0.5 if other factors like tubal disease, endometriosis or abnormal sperm parameters are present.

• Normally , no ART procedure should be used in a woman below 20 years

• No ART procedure shall be done without husbands consent

• For a sperm donor , accepted age shall be between 21 and 45 years

To look for the cause

Female Factor Male Factor

Anovulatory

Tubal Endometrial Adhesions

Medical factorsPsychological factors

Anovulatory InfertilityWHO CRITERIA

GP I :- FSH, LH Dysfunction at the level of hypth. & Pit

GP II :- (N) FSH (N) E2

GP III :- Ovarian Failure FSH

E2GP IV :- Prolactin

GP V :- Out flow tract defect.

WHO GP II

Most commonly found All PCOS present with this type of anovulation

1) Oligo Ovulation:- Ovulation once in 35-180 days

2) Anovulation:- No ovulation for 6 months

3) Hyper androgenism :- Clinical signs blood test for S.Testosterone

Androstenedione Free androgen Index

4) Oligo menorrhea

5) Amenorrhea

CHECK THE OVARIAN RESERVE

Basics of ovarian stimulation

1) Age

2) BMI

3) Baseline FSH :- (Blood Test)

4) Antral follicular count (USG)

5) AMH

FSH >10-20 Poor Response LH >10 Poor Response

E2 >60-75 Poor quality OOcyte Insulin B normal 45pg/ml

<45 pg/ml-Low reserve

USG : Antral follicle count more practical & direct approach. Superier to chronological age & endocrine markers -Eijkemans et al

B/L Ovarian <10 Follicles - Poor Response

Contd…)Contd…)

On the D2/3 of cycle

Normally follicular size at D2=3-5mm

If Follicle >15mm >15mm E2 high E2 Low

Functioning Ovarian cyst Non Functioning ovarian cyst

Rest the Cycle You can proceed cyst may regress OR Poor

ovarian response New follocle may develop

Ovarian stimulation

CLOMIPHENE LETRAZOLE

GONADOTROPINS

CLOMIPHENE

• Dose for normal women 50-100 mg/day less sensitiveUpto 250 mg/day Extremely sensitive 25 mg/ day• No advantage in using dose > 150 mg• Start with 100 mg will reduce the Tt time• 75% of pregnancies occur with in first 3 cycles• 80% will ovulate• 30-45% will get pregnant• 20-25% will not respond at all

• Can be started on Day 2/3/4/5 does not influence results

Clomiphene as a choice

• Mainly in Irregular ovulation WHO type II , PCOS

• Anovulatory Infertiliy• In ovulating women with Unexplained

Infertility CC+ IUI – Increase pregnancy ratesCC may overcome subtle defects in

ovulatory functions, inc the no. of mature follicles.

Why my patient did not respond to CC

• Obese BMI high• Insulin resistant • Hyper androgenic • LH high• Persisting luteal cyst• WHO gp I anovulation- Abn Hypoth./Pituitary• WHO gp III anov - premature ovarian failure• WHO gp IV anov - High prolactin

What can be done

• Extended Clomiphene

• Insulin sensitizing agents-Metformin

• Addition of Cabergoline/bromocriptene

• Gonadotropin

• Sequential CC + Gonadotropin

• Ovarian drilling

• Aggressive weight loss

Extended Clomiphene therapystair step protocol

• Day 3-7 Begin CC 50 mg/day• Day 7-14 USG Follicular study• Day 14 Small Follicles• Day14-18 CC 100 mg/day • Day 19 USG Follicular Study Day 22-26 CC 150 mg/day USGTotal time stairstep protocol 28 daysTraditional protocol 88 days

Side effects of Clomiphene

• Multiple follicles

• Multiple pregnancies

• Bloating & abdominal distension

• Ovarian cyst formation

• Hot flashes( DISTURBED SLEEP) 10%

• Visual disturbances 5%

blurred vision , flashes of light

LETRAZOLE

• Dose 2.5 to 5mg/day for 5 days• Start on cycle day 3/4/5 • No effect on cervical mucus or endometrium• Monofollicular ovulation • Many trial have proved letrazole giving more

pregnancies when used alone or with gonadotropins

• Still evidence–based medicine is needed to use it as first line of treatment

Stimulated with Stimulated with CC/LetrazoleCC/Letrazole

IUIIUI

Anovulation/ IrregularovulationAnovulation/ Irregularovulation

For Better Results

STIMULATED IUI

• Indication: Women with regular (25-32days) ovulatory cycles &

patent Fallopian tubes.

• Male partner must not have severe male infertility <5X106 motile sperm/ml. Mild to moderate male factor is not excluded &these couples often conceive readily.

(Contd…)(Contd…)

Not meant for:

• Women >38yrs.• Women with short cycle (<25 days) & FSH >12

iu/l• Women with Normal FSH but LH 10 iu/l• Woman with irregular cycles & severe

anovulation• Women with raised basal FSH & LH >8iu/l• Women with H/o severe endometriosis • Women with H/o abdominal surgery• Women with partner with severe male factor

unless using donor sperm.

HOW DOES IUI HELP

Treatment is designed to

1) Synchronise the timing of ovulation & sperm deposition

2) Marginally increase the number of oocytes available for fertilisation

3) Place the sperm in a closer approximation to the oocyte

Over response with ovarian stimulation for IUI

>3 FOLLICLES >16 mm

Cycles Cancelled

OR

follicle reduction / cont. to IVF

Next attempt IVF: Long protocol

IUI IN OLDER AGE GROUPS

# Older women needs more aggressive stimulation >39.

# Although occasional pregnancies will occur if older women are treated with SIUI, this will waste critical time for the majority.

Case 1• 27yrs old female.• Married for 3 years

• Attempting for 16months.• No. contraception taken• Regular menses , mild dysmenorrhea that responds to NSAIDS.

• Physical ex:- no cervical/adnexal tenderness.• Vaginal/ semen culture- negative for infection.

• Priliminary test Day 3 :- FSH,LH

E2 Semen analysis

What other test

HSG Why?

Infertility 3yrs without OC Young age

Rt. Sided proximal tubal obstr.Lt. sided patent Tube.

Cause 1) Spasm 2) Tubal Obstr

Tubal flushing Saline Sonography IUI+

with gonadotrophins6 Cycles of Clomiphene citrate + IUI

Failed to Conceive

Laparoscopy IUI with gonadotropins

Reveals ext. Adhesion with endometriosis.

IVF

Laprotomy with With severe endomertriosisLyses of adhesion & ext. adhesion IVF-ET offers& resection/ablation best pregnancy rates & Of endometiosis avoid risk of surgery.

Case 2

• 37yrs old P1+Ao• 2 yrs of sec. Infertility• O.C for 5 yrs• Stopped O.C 2yrs ago.

She presented to her gynecologist 5 months ago with c/o infertility.

Test offered: D3 :- FSH E2 Semen Analysis

(Contd…)(Contd…)

Aggressive workup needed considering (her age)

2 cycle of CC with timed intercourse

Now What?

Do you encourage CC with Gonadotropin HSG/More cycle of CC IUI With IUI LaparoscopyWith timed intercourse?

3 more cycle of IUI with CC

»Failed to become pregnant.

HSG Laparoscopy Gonadotropinc with IUI

HSG Done

B/L patent tube with no intrauterine fllling defect.

Gonadotropins +

IUI Patient became pregnant in the second cycle of IUI

Case -3• Pts Age 44yrs Male partner-49 yrs• ML 17 years• P0A1 last abortion 7 years back, 5wks gestation• HSA Tmc 70 million, 43 % Am• HSG (2007) B/l tubes patent• FSH 28 mIU/ml• LH 12 mIU/ml• She has had 3 IUI’S IN THE LAST 6 MONTHS

Few Laparoscopy IVF-ET more and with IUI’s hysteroscopy donor Oocyte/

Embryo + IUI + Gonadotropins Gonadotropins

As treatment revolves around these basic parameters,we

have answers for all our failures and as we work on our

patient, we know• Age

• Weight

• Duration of Infertiliy

• Previous treatments offererd for infertility

Poetry of reproduction will go on…..

Thank you