1. Ovarian stimulation - Overview Dr.Mridula A. Benjamin Dept of Obs and Gyn RIPAS Hospital, Brunei

2. Objective To highlight the rationale, principles and different protocols of ovarian stimulation in cases of intrauterine insemination (IUI)

3. Ovulation Day 14 Wall of Graafian follicle ruptures Ovulation 1 st meiotic division is completed

4. Cycle of ovulation and menstruation Insert fig. 20.35

5. Physiological key point Normally: A cohort of primordial follicles Continuously initiating follicular growth (Independent of Gn stim. = intrinsic mechanism) Preantral stage Need FSH in appropriate level Pre- ovulatory stage  E + FSH  FSH receptor content Dominant follicle  E  FSH  atresia of less developed foll.s Ov. stim Disturb mechanism Many follicles

6. Aim of COH Regulated superovulation by turning off the patient’s own HPO system (down regulation) followed by stimulation. 1. Recruiting multiple follicles 2. Control timing of ovulation (eggs can be surgically retrieved before they are ovulated) 3. Prevention of premature LH surge 4. To time the insemination 5. Increase the pregnancy rate

7. Monitoring To time HCG injection Decreases OHSS Decreases multiple pregnancy Follicular monitoring from D9 S. estradiol levels did not give any additional information in various studies

8. Monitoring ovarian stimulation  Transvaginal ultrasound scanning :. No. & size of follicles. Pattern & thickness of endometrium  Estrogen blood level

9. Optimum ovarian stimulation for IUI 2 – 3 follicles with Ø 18 – 19 mm. Endometrium  9 mm thick & trilaminar. IUI between Cycle D13 and D16, 36-40 hrs. from HCG inj. Cancellation :  6 follicles  15 mm irrespective of E2 level

10. 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

11. Drugs for ov. stim. Anti oestrogens: Clomiphene Citrate, Tamoxifen Gonadotrophins: HMG highly purified ur FSH Rec. FSH GnRH (pulsatile) GnRHa (intranasal-S.C- I.M) GnRHa (intranasal-S.C- I.M) GnRH ant (involved in final steps of oocyte maturation) GnRH ant (involved in final steps of oocyte maturation) HCG HCG Bromocriptine, Metformin, Letrozole Bromocriptine, Metformin, Letrozole

12. Which drug to choose for IUI? Drug Cost, Drug availability and Patient acceptability CC is effective for young women with good prognosis Remaining cases hMG or FSH would be the preferable drug rFSH Vs Urinary preparations: no difference in clinical pregnancy rate No advantage in routinely using GnRh-a in conjunction with gonadotrophins for ovulation stimulation At the moment one should use the least expensive medication.

13. Anti Estrogens Clomiphene Most widely, 35 yrs. 1962  Ease of adm., minimal side effects  Clomiphene is a triphenylethylene derivative distantly related to diethylstilbestrol The commercially available form is dihydrogen citrate salt (clomiphene citrate) Contains two stereoisomers: zu-clomiphene (38 %) and en-clomiphene (62 %)

14. Pharmacology Selective estrogen receptor modulator (similar to tamoxifen and raloxifene) Competitive inhibitors of estrogen binding to estrogen receptors Mixed agonist and antagonist activity depending upon the target tissue

15. Mech of action Pituitary action: Increases the gonadotropin response to GnRH Ovarian actions: Secondary to effects of elevated FSH and LH on ovarian follicular development Uterus, cervix, and vagina: antiestrogen Cervical mucous: decrease in the quality and quantity of cervical mucous with doses 100 mg/day

16. Indication WHO class 2 Subfertility secondary to oligoovulation Anovulation in normogonadotropic Normoprolactinemic Euthyroid women Polycystic ovary syndrome

17. Dosage Usually first line drug Normal estrogenized females 50 mg D2- D6 Max dose 200mg Same dose at ovulation for 6 cycles Ovulation- 60-85%, preg- 30-40% No increase in abortion / cong. malformation

18. Problems with CC Long lasting (till 14-22 day of cycle)  subclinical pregnancy loss compared to normal population  LH sec > FSH   miscarriage Anti E (cx &endometrium) Side effect :-Minor (nausea, vomiting, flush, hair loss, disturbed vision, bloatedness), OHSS, multiple pregnancy- 5%, ovarian ca

19. Tamoxifen 20-40 mg D2- D6 Not licensed As effective as Clomiphene

20. Unlike CC – Gn acts directly on the ovaries HMG Highly purified ur FSH (Metrodin – HP) Rec. FSH (Gonal – F, Puregon) Gonadotropins

21. 1. CC 2. CC ± FSH or ± HMG 3. Gn. Standard step-up protocol 4. Gn. Low dose step-up protocol 5. Gn. Low dose step-up, step-down protocol (Sequential) Protocols

22. Unripe follicle Ripening follicle OvulationCorpus luteum Regression of Corpus luteum Clomiphene 100 mg day2 for 5 days Gonadotrophin stimulation from day 4 to day of HCG HCG Leading follicle > 18mm Oocyte mature 38 hrs

23. Days7142128 hCG 150 IU112.5 IU 75 IU hCG Foll.  10 mm 75 IU 112.5 IU 150 IU 612 75 IU hCG Foll.  14 mm ½ FSH regimen 75 IU 112.5 IU 150 IU Chronic low dose step up Step down Sequential

24. Complications  Multifetal pregnancy (36%) OHSS (14%)- Life threatening More common in Young/ lean/ low BMI/ PCOS HCG triggering Prev. OHSS Pregnancy

25. Insulin sensitizing drugs Metformin Oral, 1500-2000mg Hyperinsulinaemia, hyperandrogenaemia RCT- clomiphene resistant pts., use of metformin & CC produced significant improvement Recent study- Letrozole & metformin also showed promising results Metaanalysis of metformin co-adm during gonadotrophin induction in PCOS has been inconclusive

26. Aromatase inhibitors Letrozole- 3 rd generation 2.5mg OD/BD on D3-7 Breast cancer in postmenopausal for several years Lacks unfavourable effects on endometrium seen with CC Initial evidence is encouraging, but larger trials are required

27. Hyperprolactinaemia Dopamine agonists- bromocriptine, cabergoline No MP, no monitoring Cabergoline more effective Micro- 80% / 85% Macro- 65% / 50% N, V, vertigo, hypotension, headache, drowsiness

28. GnRH analogues GnRHa - high levels of LH Metaanalysis - no clear advantage of routine use in conjunction with gonadotrophins in pts. with clomiphene resistant cases Increases cost, OHSS, multiple pregnancy Some say lessens overall cost by reducing gonadotrophin requirement by 50%

29. Dexamethasone or OCP ?? Improves pregnancy rates in anovulatory women in WHO group 2 with DHEA-S levels greater than 2.0 mcg/ml OCP to regularise the cycles before stimulation Meprate withdrawal

30. Surgical Laparoscopic ovarian drilling Armer’s criteria Ovulation- 90% Pregnancy- 70% One step treatment Within one year Reduced MP & OHSS

31. Ovulation trigger Natural cycle- raised Oestradiol leads to LH surge Ov. stimulation- unpredictable HCG( pregnyl, Profasi) Recombinant form available(Ovitrelle) 5000- 10,000 IU S/C Causes higher luteal phase conc. of progesterone.

32. Conclusion Ovarian stimulation is the fundamental tool of subfertility treatment Different options pose challenges Choice depends on doctors expertise and patients condition, choice Increases the pregnancy rate Time the IUI Judicious monitoring to avoid complications

33. Thank you