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
1st meiotic division is completed

4. Cycle of ovulation and menstruation
Insert fig

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

6. Aim of COH
Regulated superovulation by turning off the patient’s own HPO system (down regulation) followed by stimulation.
Recruiting multiple follicles
Control timing of ovulation (eggs can be surgically retrieved before they are ovulated)
Prevention of premature LH surge
To time the insemination
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, 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)
GnRH ant (involved in final steps of oocyte maturation)
HCG
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 %, preg %
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. Gonadotropins Unlike CC – Gn acts directly on the ovaries HMG
Highly purified ur FSH (Metrodin – HP)
Rec. FSH (Gonal – F, Puregon)

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

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

23. FSH regimen hCG hCG ½ hCG Chronic low dose step up Step down
150 IU
112.5 IU
hCG
75 IU
75 IU
Days 7 14 21 28
Step down
150 IU
112.5 IU
75 IU
hCG
Foll.  10 mm
Sequential
150 IU
112.5 IU
75 IU
75 IU
hCG 6 12
Foll.  14 mm

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, mg
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- 3rd 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)
,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