Ovarian Ageing and Fertility Dr. Sharda Jain Secretary General Delhi Gynaecologist Forum HOD, Puspanjali Crosslay Hospital

Reproductive organs Ovary Uterus Passive organ Responds to endogenous or exogenous hormones for ever No senescence Active organ with fixed deposit of oogonia at birth Once fixed deposit is over no response to endogenous or exogenous hormones menopause

Why ovarian ageing? Birth: 1-2 million oogonia Puberty: 3 to 5 lac oogonia menopause: Follicular exhaustion (number of resting follicles below 1000) ovulation500 atresia3-5 lac In healthy woman accelerated loss & accelerated qualitative decline of follicles start at 37.5 years when only 25000 resting follicles remain in ovaries. Fertility , both natural and assisted, declines rapidly after 37.5 years and almost becomes zero at age 41.

DIAGNOSIS OF POOR RESPONDERS RETROSPECTIVE TWO ATTEMPS OF COH IN SUPEROVULATION PROTOCOLS <3 DOMINANT FOLLICLES E2 LEVELS OF < 1000 PG/ML.

PROFILE OF POOR RESPONDER age> 35yrs Unexplained infertility Clinical history consistent with previous ovarian damage Prior cycle cancellation due to poor response Women nearing end of reproductive life and having menstrual problems

Other causes of premature ovarian ageing (poor responder)? H/o Early menaupause (F/H) Smoking Pelvic inflammatory disease Endometriosis Chemotherapy Pelvic surgery and not just ovarian surgery HIV and hepatitis Prolonged use of ocp! myth?

Types of Tests to Predict Ovarian Ageing CHRONOLOGICAL AGE ENDOCRINE TESTS Basal FSH, E2, FSH:LH ratio, Inhibin B and AMH levels ULTRA-SONOGRAPHY Ovarian volume and AFC DYNAMIC TESTS CCCT GAST EFORT INVASIVE TESTS

AGE ↓ NO. OF OOGONIA & DECLINE IN OOCYTE QUALITY Tietze & Hutterite: women in Canada and USA:11% cease having children at 34 years, 33% no pregnancies after 39years and extremely rare pregnancy after 45 years POOR IMPLANTATION AND ↑ CHANCES OF ABORTION Virro etal.,1984; HIGHER RISK OF GENETIC ABERRATIONS: Lim AST , Fertil Steril 1997: rate of genetic aberration 24% in < 34 years, 52% b/w 35-39 and 95.8% in age > 40 years

D3 FSH ↑10 IU/L are considered ABNORMAL BASAL FSH D3 FSH ↑10 IU/L are considered ABNORMAL - Correlates with fewer available oocytes - Poor outcome with IVF No statistical variation in predictive value of D2 to D5 FSH in regular cycles Fluctuating FSH values indicates poor ovarian reserve

BASAL FSH LARGEST RETROSPECTIVE STUDY OF 758 IVF CYCLES FSH < 15 miu/ml- PR 17%, FSH 15-24.9: PR 9.3% FSH> 25 : PR 3.6% Scott RT , Fertil Steril 1995

D3 Estradiol: > 60 pg/ml BASAL E2 D3 Estradiol: > 60 pg/ml Difficulty in achieving pregnancy Characterstic of years preceding menopause BENEFICIAL IN SCREENING FOR POTENTIAL POOR OVARIAN RESPONDER IN CASES WITH NORMAL FSH VALUE

↓ false negative results BASAL E2 DAY3 E2 CAN VARY AS MUCH AS 40% WHERE AS D2 TO 4 FSH SHOWS ONLY 18% VARIANCE EARLY PREDICTION COMPARED TO BASAL FSH FSH & E2 (combined)- ↓ false negative results

BASAL E2 ≥ 60 pg/ml Liccardi etal , Fertil Steril 1995 NO PREGNANCY with basal E2 >75, Maximum pregnancy with E2< 30 Smotrich etal , Fertil Steril 1995, No Pregnancy with E2>100, lower PR ,↑cancellation with E2 > 80 ≥ 60 pg/ml

FSH: LH FSH: LH> 3 despite normal FSH values may help to identify poor ovarian responder Fewer oocytes retrieved, lower implantation rates, poor clinical PR Barroso G etal 2001; LH / FSH ≥ 2 / PCOS

HIGH LH >10 MIU/ML: INDICATES POOR RESPONSE - PCOD - IR

BASAL INHIBIN B ≤ 45 pg/ml Direct measure of ovarian reserve. levels ≤ 45 pg/ml correlates well with lower PR Seifer et al, Fertil Steril 1997,1999; Danforth et al.,1998; Fried et al.,2003. All studies do not support its use as clinical marker Hall et al.,1999; Creus et al.,2000 Follicles of obese women produce less inhibin B as compared to lean women Low inter-cycle variation compared to FSH ≤ 45 pg/ml

ANTI MULLERIAN HORMONE (AMH) AMH is produced by granulosa cells of small antral follicle till they become sensitive to FSH AMH disappears at menopause or after oopherectomy AMH levels of less than 1.1 associated with IVF failure ANTRAL COUNT

ULTRA-SONOGRAPHY Ovarian volume is an independent predictor of IVF outcome (N-7 cc) Volume <3 cc-predicted 50% cancellation rate Antral Follicle Count: <5 in no- inactive ovaries 5-10 in no: normal >15: PCO

INVASIVE TEST OVARIAN BIOPSY FOR FOLLICLE CONCENTRATION

DYNAMIC TESTS OF OVARIAN RESERVE Clomiphene Citrate challenge test (CCCT) Gonadotropin agonist stimulation test (GAST) Exogenous FSH ovarian reserve test (EFORT) No test absolute Poor prognosis Helps in decision making process.

CLOMIPHENE CITRATE CHALLENGE TEST (CCCT) 100 mg clomiphene D5-9, FSH on D3 and D10: abnormal test defined as abnormally high FSH on D3 and/or D 10 Navot etal 1987 Assesses ovarian reserve in women with intact HPO axis 94% accurate and beneficial in unexplained infertility 2-3 times better pick up rate than basal FSH. Recent meta-analysis shows CCCT equal to basal FSH as predictor. Jain et al 2004

CLOMIPHENE CITRATE CHALLENGE TEST (CCCT) Prevalence of abnormal test – 10% ↑ with - ↑ age ↑ ↑ - unexplained infertility Normal Day 3 FSH & ↑ Day 10 FSH – same poor results as of ↑ Day 3 FSH ≥15-17 MIU/ML ON Day 10 Poor Prognosis - PAI

GnRH AGONIST STIMULATION TEST (GAST) Evaluates change in serum E2 between D2 and D3 after s/c administration of 1 mg of Leuprolide acetate E2 elevation by D2 and decline by D3 had better implantation and PR No rise or persistent elevation : poor implantation and pregnancy rate Padilla etal

EXOGENOUS FSH OVARIAN RESERVE TEST (EFORT) E2 level is assessed on D3 and then 24 hrs after administration of 300 IU of purified FSH Increase in E2> = 30pg/ml predictive of good response in subsequent IVF cycle

HOW TO TREAT POOR RESPONDER? Ovulation induction CC followed /overlap with HMG High dose HMG (4 to 6 amp/day) from day 2-3 GnRH agonist with HMG Short protocol Flare up protocol Mini dose GnRH agonist for long protocol down regulation Antagonist protocol

ADDITIVES TO IMPROVE RESPONSE Growth hormone GH releasing factor

CONCLUSIONS IDEALLY FSH SHOULD <10MIU LH <8MIU E2 <5O PG

CONCLUSIONS FSH >20 MIU NO HOPE WITH DRUGS

FSH 10-20 IU/ML (COMMONLY SEEN AT 35-40 YERS) BODERLINE RESPONSE TO STIMULATION. BUT MOST OF THE CASES MAY NOT RESPOND TO G.T. STIMULATION. LARGER DOSES OF GT HAVE TO BE USED-------- LESS RESPONSE OF OVULATION.

E2 LEVEL >60 PG/ML IT INDICATES FOLLICLE FUNCTIONING AT ACCELERATED LEVELS AND THESE CYCLES OFTEN YIELD OOCYTES OF REDUCED QUALITY.

POOR RESPONDERS >35 YEARS D3 FSH >10 – GUARDED APPROACH - >20 – NO HOPE D3 E2 >60-80 PG/ML FSH: LH >3 D3 LH <3 MIU/ML

POOR RESPONDERS INHIBIN ≤ 45 PG/ML USG O.VOL. <3 CM3/AFC <5 CC CHALLENGE TEST ↑D3 , 10 FSH - ≥ 17 Extremely Poor Response

IVF Patient with diminished ovarian reserve (FSH >15 miu/ul) should be discouraged from undergoing IVF with their own egg. Oocyte donation offers high success rate in cases with >15 FSH and E2 > 80

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