Ovulation Induction & IUI DR NABANEETA PADHY MEDICAL DIRECTOR FEMELIFE FERTILITY FOUNDATION www.femelife.com www.wikiHealthNews.com

Significant increase in live birth rate was found when hyperstimulation was compared with IUI in natural cycle in women with Unexplained Infertility Cochrane Systematic review 2008 ; issue 2 However concern about multiple pregnancy and OHSS remains

IUI with controlled OH significantly improved the probability of conception in subfertility in men Conchrane database Syst Rev . 2007 However in case of severe semen defect ( with < 1 million motile sperm after semen preparation ) IUI in natural cycle should be the treatment of choice.

What ? When ? To Whom ? How ?

To Whom ?

Absent Ovulation Infrequent Ovulation Inadequate FSH stimulation Inadequate corpus luteum function PCO Unexplained infertility To time the Ovulation To increase the number of oocytes IVF / ICSI

Every lady entering in Infertility centre receives ….

INDUCTION OF OVULATION * ANOVULATORY CYCLES * DYSOVULATORY CYCLES * NORMAL OVULATORY CYCLES

When ? www.femelife.com www.wikiHealthNews.com

(gonadotropic independent folliculogenesis ) It takes about 10 wks for the primordial follicle to develop into preantral stage, which is then capable of gonadotropic responsiveness . (gonadotropic independent folliculogenesis ) A cohort of these preantral follicles start growing due to rising FSH. One of them becomes the dominant follicle (by day 6) which in turn by producing increasing amount of estrogen, decreases FSH production through negative feedback causing atresia of less developed follicles.

Dominent follicle

The role of ovulation inducing agents - to disturb this normal relationship by increasing the FSH above threshold which will rescue a follicular cohort ( before they undergo atresia) Hence more number of follicles will reach to the preovulatory stage.

Dominant Rescued drug

How much ?

* Age * Weight * Day 2 FSH * Ovarian volume & Antral follicle index

What ?

Clomiphene Citrate : selective estrogen receptor modulator

75 % of conceptions occur during first three cycles * 75 % of conceptions occur during first three cycles . When no pregnancy is achieved within 6 treatment cycles alternative therapy should be chosen. * Clomiphene should be used for maximum of 12 months in patient’s life time and for a maximum of 6 months consequently.

* Dose more than 150 mg leads to hypoestrogenic effect on endometrium. * CC does not appear to increase the chances of pregnancy in women who ovulate regularly but failed to conceive after 1 year of unprotected sex.

Drawbacks : Despite high ovulation rate, low pregnancy rate Multiple pregnancy : 10 % Antiestrogenic – detrimental to sperm transport and embryo implantation. Sometimes risk of OHSS

5.The effect lasts longer , may be for weeks even with a single dose of 50 mg. Its presence at the time of ovulation inhibits progesterone formation by granulosa cells in luteal phase 6.Can give premature LH surge due to supraphysiological estradiol levels 7. Cannot be used in patients with hypogonadotropic dysfunction

In search of better drug with improved pregnancy rate , reduction in the incidence of multiple pregnancy rate & ……

Failure with or Resistance to CC

Alternative / Adjuvant Treatment for CC Cochrane review 2005 Jan Included 12 RCTs

* Tamoxifen * Dexamethasone * Bromocreptine * Aromatase Inhibitor * Insulin Sensitisers * Oral Contraceptive Pretreatment * Gonadotropins

* CC + Dexamethasone resulted in significant improvement in PR in CC resistance cases. * Significant increase in PR in CC cycles when pretreatment with oral contraceptives than CC alone in PCOS

* Aromatase Inhibitor * Tamoxifen * Dexamethasone * Bromocreptine * Oral Contraceptive Pretreatment * Aromatase Inhibitor * Insulin Sensitisers * Gonadotropins

Letrozole non steroidal selective estrogen enzyme modulator

In last few years , it has added another option for the ovarian stimulation

First report by Casper and Mitwaly group in 2001 , saying , “ Preliminary evidence suggest that AI may replace CC in future because of similar efficacy and less side effects. ”

Aromase Inhibitor Treatment

* Inhibition of estrogen synthesis by aromatase inhibition - release estrogenic negative feedback (Mitwally and Casper 2001) * Accumulation of androgens locally may increase follicular sensitivity to FSH (Vendola et al 1998)

Clomiphene Vs Letrozole

Results CC is superior to AI as first line of treatment Both have equal results as far as ovulation rate, and pregnancy rates are concerned Letrozole can replace CC as first line of treatment

Why to prefer ?

* Short half life * Implantation rates improve with the reduction of supra-physiologic level of estrogen associated with COH,which is believed to have deleterious effects on the embryos or the endometrium * Reduction of estrogen levels during induction cycles may prevent a premature surge of LH

* Letrozole is safe, convenient, inexpensive and has the potential to replace Clomiphene as the first line of choice for OI, especially when it has to be used along with gonadotropins * Letrozole used with sequential FSH administration significantly reduces the FSH dose for COH & hence becomes cost effective therapy

* Improvement is seen in ovarian response to FSH in poor responders

* Tamoxifen * Dexamethasone * Bromocriptine * Aromatase Inhibitor * Gonadotropins * Insulin Sensitisers * Oral Contraceptive Pretreatment

When to use gonadotropins ?

Failure with or Resistance to Oral OI drugs

On evaluating effectiveness of IUI , pregnancy rates are significantly higher in women who received gonadotropins Hughes 1997, Cohlen 1998 , Guzick et al 1998

Reducing the dose of gonadotropins without compromising pregnancy rate would definitely reduce the overall costs & possibly improve the cost effectiveness of IUI treatment

Stimulating endogenous gonadotropin production with sequential use of lower doses of exogenous FSH for COH Mitally & Casper

Multiple Pregnancy Rate Mitwally et al, AJOG 2005; 192(2): 381-6 Percent Multiple Pregnancy Rate Mitwally et al, AJOG 2005; 192(2): 381-6 CC+ FSH Let + FSH Letrozole 2.5 mg Letrozole 5 mg CC FSH

Adjunctive Therapy with FSH in poor responders Mitwaly and Casper (2001) examined the use of Letrozole with FSH for poor responders undergoing ovarian superovulation and IUI Letrozole 2.5 mg/day from Day 3 to Day 7 was used with FSH(50-225 IU starting on day 7) * Significant reduction in the FSH dose * An improvement in ovarian response to FSH

Comparison of daily and alternate day rFSH stimulation protocols for IUI Tulandi T ,et al Fertil Steril 2008 March * Total dose needed was greater in daily injection group * CPR was 42% in daily inj group Vs 19% in alternate –day group

* Tamoxifen * Dexamethasone * Bromocreptine * Aromatase Inhibitor * Gonadotropins * Insulin Sensitisers * Oral Contraceptive Pretreatment

The recognition that Insulin Resistance has a pivotal role in the pathogenesis of PCOS revolutionalized our understanding of this complex disorder

Metformin combined with CC is more effective in ovulation induction as compared with CC alone especially in obese PCOS Cochrane review Jan 2008 However , the optimal duration for metformin treatment before initiation of CC is unknown as in Cochrane review they could not find any data over short term Vs long term metformin pretreatment.

Use of Metformin in PCOS : Metanalysis Metformin alone, CC alone & Met + CC Outcomes : Ovulation rate , PR & LBR Conclusion : Metformin improved the odds of ovulation in women with PCOS when compared to placebo When combined , there is increase in ovulation & PR especially in obese PCOS & CC resistance cases.

EBM : 1.There is evidence that metformin is effective in restoring ovulation in anovulatory cycles with PCOS 2. It is more cheaper option than laparoscopic ovarian drilling as the second therapeutic step in PCOS with CC resistance 3. Coadministration of metformin can prevent hyperstimulation in PCOS on treatment with gonadotropins in IVF cycles

GnRH Antagonist in IUI

* In cases of premature LH surge * To time weekend IUI

Ovurelix 0.25 mg/day is given from the day when follicle reaches to size of 14 -15 mm till hCG administration

Conclusion

CC was the first line of treatment for OI for many decades. In CC resistance cases , Metformin + CC & Dex + CC has shown significant improvement in PR and got upper hand in treatment of CC resistance over laparoscopic drilling AI have the potential to replace CC as the first line of treatment with its several advantages

4. Addition of low dose gonadotropins to oral ovulogens significantly improves PR in IUI 5. Letrozole is superior to CC whenever gonadotropins have to be added 6. There is no role of Bromocriptin in CC resistance cases with normal prolactin levels 7. Pretreatment with OC pills is useful 8. Tamoxifen and CC has comparable results but combination of two does not improve PR

9. GnRH Antagonist is of great value in cases of premature LH surge.

Case 1 26 yrs old, married for 3 yrs, laparoscopy done , Found to be PCOS. Drilling done , semen analysis shows count 10 million with rapid motility 10% What next- IUI or not Case 1

Case 2 25 yrs old female , primary infertility ,prolactin level is 56 pg/ml How to manage Start bromocriptine/ pergolides or not

Case 3 Day 3 LH for a 25 yr old is 7 IU Drugs to be used for ovulation induction ?

Case 4 Young couple , patent tubes, male factor normal, ovulation induction and IUI done for 3 cycles , failed What next ?

Case 5 Young couple , h/o ectopic pregnancy twice affecting both tubes, but managed medically. Recent HSG shows bilateral patent tubes Shall we proceed for IUI ?

Case 6 38 yr old lady recently married , asking for IUI HOW TO COUNSEL ?

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