OVULATION INDUCTION

DR SEENIAMMAL GOVT MEDICAL COLLEGE CALICUT

INTRODUCTION
 Incidence of infertility in India - 15.07% (Zagar et al 1997)  Ovulatory dysfunction - 15% of infertile couples

- 30-40% of female infertility

WHO CLASSIFICATION Ovulatory dysfunction

 Group - - Hypothalamic Pituitary Failure
(Hypogonadotropic hypogonadism)

 Group II Hypothalamic Pituitary Dysfunction

(Normogonadotropic normogonadism)
 Group III Ovarian Failure

(Hypergonadotropic hypogonadism)

DEFINITION
Therapeutic restoration of ovulation in anovulatory woman by selection of a single dominant follicle followed by monoovulation (ESHRE Capri Workshop Group, 2003)

OVULATION INDUCTION
 In infertility due to

normogonadotropic normogonadism
 Serum prolactin is normal

 Etiology:
PCOS ( 70% of the cases) Luteal insufficiency

Approach to Ovulation Induction in PCOS

PCOS Overweight or obese Weight reduction Ovulation Ovulation No Ovulation Clomipene citrate (CC) No Ovulation CC & metformin OR CC & dexamethasone OR Aromatase inhibitors OR Ovarian drilling No Ovulation Ovulation Gonadotropins OR IVF Lean

COG 2007

ANTI ESTROGENS
 Clomiphene citrate  1st synthesized in 1956  Long t = 5 days to 3 weeks

MECHANISM OF ACTION

CLOMIPHENE CITRATE -DOSE

 Given for 5 days- from days 2, 3, 4 or 5

no diff. in the outcome between these time points

(Wu and Winkel, 1989)

 Recommended dose - 50 mg/day  Maximum dose - 150 mg/day  Ideally upto 6 cycles (never more than 12 cycles)

ACOG

CCCC-RESULTS OF THERAPY
 Ovulation induction rate 70 90%

Pregnancy rate is lower 30 40% (Messinis et al,2002)

 Multiple pregnancy rate is 6 8%

OHSS is a rare event

 Clomiphene resistance -10-30%

(Adashi, 1996)

(Hughes et al, 2000)  Clomiphene failure -when pregnancy is not achieved despite ovulation

METFORMIN
 BMI> 25 - metformin + CC 

[RCOG]

sensitivity of peripheral tissue & liver to insulin 1500-2500mg/d

 Started at low dose,

 Ovulation rate - 76% with CC & Metformin

42% in CC alone

AROMATASE INHIBITORS
 Letrozole

prevents conversion of testosterone

to estradiol  Estrogenic negative feedback lost - upregulation of ER in the endometrium

 Letrozole- 2.5 mg OD for 5 days from cycle day 3

or single dose of 20 mg on day 3

 t1/2= 45 hrs

LETROZOLE VS CLOMIPHENE CITRATE

TulandiT Fertil Steril. 2006

 Congenital malformations & chromosomal

abnormalities -2.4% of the letrozole group 4.8% in the CC group

 The concern that letrozole use for ovulation induction

could be teratogenic was unfounded India banned the usage of Letrozole in Nov 2011, citing potential risks to infants

GONADOTROPHINS
 Introduced in 1961  Preparations hMG, purified FSH, r-FSH  Step up protocol
Conventional protocol - starting dose FSH 150 IU/d multiple pregnancy rate - 36 % OHSS-14%

LOW DOSE STEP UP PROTOCOL

Starting dose = 37.5-75 IU/day 37.537.5-75 FSH/hMG/day

Day 3

5 days

Day 7 Follicle > 12 mm E2 > 400US

Continue 1 FSH/day

If no response p 150IU /day

for 1 more week

LOW DOSE STEP-DOWN REGIMEN STEPhCG 2 FSH/d

1 FSH/d
2-3 days
U/S U/S

1 FSH/d

Day 3 3-4 amp. U/SD7E2 U/S& E2 &

Foll >11 mm Foll >11 mm

150 IU

112.5 IU

75 IU

GONADOTROPHINS-RESULTS
 rFSH vs uFSH in PCOS
No significant differences in terms of ovulation, pregnancy, miscarriage, multiple pregnancy rate & OHSS
Cochrane 2001

OTHER DRUGS
 PULSATILE GnRH
Outcome of treatment poor in PCOS

 GnRH agonists
To suppress basal LH values when elevated Studies demonstrated an increased risk of OHSS
van der Meer et al 1996

GnRH ANTAGONISTS
-Short simple protocol

18

-Low pregnancy rate

flare

levels with GnRH agonist levels with GnRH antagonist

gonadotropins

Hurine Judith, Lambalk Cornelis. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001; 358: time 1793-803

LAPAROSCOPIC OVARIAN DRILLING

 Started in 1984 by Gjnnaess  Ovarian drilling- diathermy points 4 per ovary

for 4 sec at 40 watts

 Mechanism of action

Destroys androgen producing ovarian stroma E2 -- negative feedback to FSH & positive feedback to LH normal LH/FSH ratio

LOD - Outcome
 Spontaneous ovulation rate- 70% to 90%  Conception rate -55% to 65%

LOD vs Gn treatment Clomiphene resistant PCOS

No difference in live birth rate & miscarriage rate multiple pregnancy rates
Cochrane 2005

PROBLEMS OF OVULATION INDUCTION

 Hyper responders: OHSS & multiple pregnancies  Poor responders  Premature LH surge  Poor endometrial development  Ovarian cancer  Breast cancer

TO CONCLUDE
 Restoration of monofollicular development &

mono-ovulation
 Intensive monitoring is mandatory  Conventional ovulation induction - highly effective

treatment sequence
 Treatment response is determined by individual

patient characteristics
 Patient-tailored treatment gives optimal results

REFERENCES
1.

Scott RT, Leonardi MR, Hofmann GE, et al. A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population. Obstet Gynecol 1993;82:539 544. Hammond MG, Halme JK, Talbert LM. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation. Obstet Gynecol 1983;62:196 202. Adashi EY. Clomiphene citrate initiated ovulation: a clinical update. Semin Reprod Endocrinol 1986;4: 255 276. Li TC, Warren MA, Murphy C, et al. A prospective, randomised, cross over study comparing the effects of clomiphene citrate and cyclofenil on endometrial morphology in the luteal phase of normal, fertile women. Br J Obstet Gynaecol 1992;99:1008 1013. Thompson LA, Barratt CL, Thornton SJ, et al. The effects of clomiphene citrate and cyclofenil on cervical mucus volume and receptivity over the periovulatory period. Fertil Steril 1993;59:125 129.

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