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

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

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

Cycle of ovulation and menstruation Insert fig. 20.35

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

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

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

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

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

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 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

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.

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 %)

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

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

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

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

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

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

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

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)

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

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 ½ 150 IU 112.5 IU 75 IU 75 IU hCG 6 12 Foll.  14 mm

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

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

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

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

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%

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

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

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.

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

Thank you