Ovarian Stimulation in IUI- Overview Dr. Jyoti Bhaskar MD MRCOG Director Lifecare IVF

Rationale for COH in IUI Increasing the number of eggs available for fertilisation Overcoming subtle defects in ovulatory function and luteal phase.

Aim of COH Recruiting multiple follicles Control timing of ovulation Prevention of premature LH surge To time the insemination Increase the pregnancy rate

Optimum Ovarian Stimulation for 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.

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

Drugs for Ovarian Stimulation Clomiphene Citrate, Tamoxifen Gonadotrophins: HMG Highly purified urinary FSH Recombinant. FSH GnRH Agonist/ Antagonist

CLOMIPHENE CITRATE Most widely Simple to use, Minimal side effects, Cost effective

CLOMIPHENE CITRATE ( SERM) Binds HYPOTHALAMUS ER GnRH Blocks ER Pituitary FSH Cervix Vagina OVARY Endometrium Folliculogenesis

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 days

CC CHECK Evaluation of the patient on Day 2 Previous cycles TVS – ET , AFC and cysts Review reports of FSH, LH if available

WITH OVULATION AND TIMED INTERCOURSE CC FAILURE ( 40%) No Pregnancy 3 CYCLES OF CC WITH OVULATION AND TIMED INTERCOURSE 2 CYCLES OF CC WITH IUI

CC RESISTANCE (20%) 3 CYCLES OF CC NO OVULATION Wt loss, extended CC, adjuvants – metformin, dexamethasone COST , PT’S CHOICE COUNSELLING CC + GONADOTROPHINS GONADOTROPHINS

Antioestrogenic Effect Thin Endometrium Poor cervical Mucus Start early in cycle – Day 2 or Day 1 Add oestradiol valearate from day 8/9 Use all gonadotrophin cycle

Gonadotrophins - Indications CC Resistance CC Failure WHO 1

Choice of Gonadotrophins HMG Highly purified Urinary HMG/FSH Recombinant. FSH Day 2 LH/FSH FSH WHO group1 LH PCOS FSH HMG

DOSE BMI Ovarian reserve Age Cause of Infertility Dose needed in previous cycle

Complications Multifetal pregnancy OHSS - Life threatening Monitoring Experience Strict protocols

Protocols CC only with TI or IUI CC ± FSH or ± HMG with IUI Gonadotrophin only Conventional regime Gn. Low dose step-up protocol Gn. step-down protocol 4. Gonadotrophin with GnRH antag

IF ET< 5MM OV 2MG BD DAILY 3 4 5 6 7 8 9 10 11 12 13 14 15 21 DAYS OF CYCLE TVS – ET AND AFC CC 100 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 Lifecare 24hrs 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

Regression of Corpus luteum Unripe follicle Ripening follicle Ovulation Corpus luteum Regression of Corpus luteum Oocyte mature 38 hrs HCG Clomiphene 100 mg day2 for 5 days Gonadotrophin stimulation Leading follicle > 18mm

Gonadotrophin Regimens Chronic Low dose Step up regimen 150 IU 112.5 IU hCG 37.5 IU 75 IU Days 7 14 21 28 Step down 150 IU 112.5 IU 75 IU hCG Foll.  10 mm Conventional Regime 75-150 U daily hCG 2 6 12 Foll.  16mm

Gonadotrophins with Antagonists 15-20% cycles with Gonadotrophins have premature LH surge

Advantages of Antagonist Protocol Helps avoid IUI at weekends Prevents premature surge Compared to agonist – simple and inexpensive Lower rates of OHSS

The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ 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 IUI Low 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. The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ 24

The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ GnRH-agonists There seems to be no role in IUI programs Increase costs Increase multiples without increasing the probability of conception Urinary gonadotrophins versus Recombinant products There is no significant difference GnRH-antagonists Whether or not are going to play a role in mild ovarian hyperstimulation/IUI programs needs to be determined in future trials. Letrozole There 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 BJ

might be the most effective drugs with IUI 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 Gonadotrophins might be the most effective drugs with IUI Low dose protocols are advised No studies using CC + gonadotrophins 26

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. 27

Conclusion Ovarian Stimulation protocol Simple Cost Effective Minimal side effects Best success rates

TIME TO MOVE ON TO TOTAL GONADOTROPHIN CYCLE 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

Thank you