What causes anovulation?

Hypogonadotrophic (hypothalamic).

(WHO I)

Eugonadotrophic. (WHO II)

-PCOS.

-Hyperprolactinemia.

Hypergonadotropic (ovarian failure).

(WHO III)

FSH threshold-window concept

The inter-cycle rise of serum FSH concentrations exceeds the threshold for rescue of a cohort of follicles for further development.

The transient nature and rapid decline of FSH rise closes the window and causes all of the rescued follicles except the dominant one from further development.

What is Clomiphene Citrate (CC)?

Triphenylethylene distantly related to DES.

The commercially available is di-hydrogen citrate salt.

Mixture of two isomers (En: Zu) in 3:2 ratio.

En-clomiphene (trans-isomer)is the active constituent.

Zu-clomiphene (cis-isomer) is slowly cleared (detected

up to 6 weeks after administration).

N-CH2-CH2-OC2H5

C2H5C=C

CL

Clomiphene Citrate

Clomiphene Citrate (CC)

Acts on estrogen receptors (E.R) as

SERM with distinct agonist-antagonist

profile.

The trans-isomer is the anti-estrogen

while the cis-isomer is an estrogen.

Tamoxifen (Nolvadex) acts like pure

trans-isomer.

Mechanism of action Ovulation initiation, not induction !!

Anti-estrogenic effect on hypothalamus release it

from estrogen feed- back and causing Gn-Rh

release.

Subsequent rise of FSH above the threshold

recruits a cohort of follicle.

Like normal menstrual cycle, rising estradiol

concentration suppresses FSH , and culminates in

LH surge triggering ovulation.

Adashi: Ovulation induction by clomiphene

citrate.

Reprod Endocrinol 1996

Window

Indications:

1. Eu-gonadotropic, normo-prolactinemic anovulation, (mostly PCOS).

2. Infertility associated with luteal phase dysfunction.

3. Infertility associated with oligoovulation.

4. Infertility requiring improved timing like artificial insemination.

5. Augmenting ovulation in ovulatory unexplained infertility.

6. In combination with hMG for superovulation.

Pre-treatment evaluation.

• TVS.• Semen analysis.• Tubal patency testing.

• TVS.• Semen analysis.• Tubal patency testing.

Clinical approach

1. Start with/without progestin induced bleeding, cycle day 2-5.

2. Protocol for graded incremental therapy.

3. 50% of pregnancies occur at the 50mg dose, additional 20% at the 100mg, so total 70% of pregnancies occur at the 100 mg dose for 5 days

1. Start with/without progestin induced bleeding, cycle day 2-5.

2. Protocol for graded incremental therapy.

3. 50% of pregnancies occur at the 50mg dose, additional 20% at the 100mg, so total 70% of pregnancies occur at the 100 mg dose for 5 days

Monitoring

1. Maryland “triple 7 regimen”.2. Ultrasound.3. Urinary L.H kits. 4. Cervical mucous method.5. Basal body temperature (BBT).6. Mid-luteal serum progesterone.

1. Maryland “triple 7 regimen”.2. Ultrasound.3. Urinary L.H kits. 4. Cervical mucous method.5. Basal body temperature (BBT).6. Mid-luteal serum progesterone.

Follicle Scanning

Follicle is dominant when its size≥12mm.Rate of follicle growth is≈2mm/day.Ovulation occurs at 22-26mm diameter.Follicles>30mm are probably cystic.

L.H KitsRheologicaldetection

Menses Day 5 to 9 Day 13-14

Foll.Endo.

Ov.Endo.

Cycle evaluation with CC treatment

36 h 5 days

HSG

CC 100 mg/d

LHFSHPRLTSHDHEAU/S

U/SE2LHPCT

? LH

U/SP4

? hCG10,000

? IUI

? Luteal support

36 h

Duration and treatment outcome-1

80% of PCOS patients will ultimately ovulate

after CC therapy and up to 50% achieve

pregnancy after 6 cycles.

Failure to achieve ovulation after 3trials is

termed clomiphene resistance, the incidence of

which can be greatly reduced by various pre-

treatments and adjuvants.

CPR continues to rise after 6 to 9 months of

therapy.

Prediction of response

Response to clomid is related to: Age. BMI. IR FAI. Cycle history. Sonographic ovarian morphology.

Ghobaldi et al Fertil steril 2007;

March:87(3)

Clomid Ovulation Failure

This is arbitrary defined as failure to ovulate on doses of 150 mg / day for 5 days (even though 10 - 20% of patients can ovulate on higher dosages, it is important to re-evaluate the patient at this stage. Clomiphene is also approved by the FDA for a maximum dose of 750 mg / cycle.)

Alternatives for CC resistance:

Increasing the dose or duration of CC.

Pre-treatment with metformin or OCPs.

The use of adjuvants like Dexamethazone.

Addition of hMG.

Low dose hMG.

Alternatives for CC resistance:

The duration might be increased to 7

days according to Isaacs et al and

even to 10 days according to Fluker

et al with reported increased

ovulation and pregnancy rates in

resistant cases.Isaacs et al Fertil Steril 1997Fluker et al Fertil Steril 1997

Duration and treatment outcome-2

Failure to achieve pregnancy despite of

achieving ovulation for 3-6 cycles is termed

clomiphene failure.

Clomiphene failure dictates discontinuation

and re-evaluation.

Clomiphene Failure might be attributed to

other overlooked subfertility factor, or

marked sensitivity to anti-estrogenic CC side-

effects.

Conclusion & take home message

CC is still the drug of the first choice for ovulation induction in PCOS.

It is appropriate to perform Basic infertility evaluation including semen analysis and HSG before induction.

Correction of underlying metabolic derangement is preferable before induction to improve response and optimize health before intended pregnancy.

Conclusion & take home message

Duration of pre-treatment should be individualized but three months (cycles) which is the duration of folliculogenesis might be appropriate.

Induced withdrawal bleeding with progestin is recommended particularly in amenorrheic patients.

Starting CC during the first 5 days after withdrawal bleeding is reported to produce best results.

Conclusion & take home message

The first CC cycle might be monitored by follicle scanning, but in subsequent cycles urinary LH kits might be used for ovulation prediction.

HCG is generally not required but might be added for certain patients.

Alternate cycle treatment for 3 to 6 cycles might be tried with hopefully increasing cumulative pregnancy rates.