Presentation on theme: "Ovarian Ageing and Fertility"— Presentation transcript:
1 Ovarian Ageing and Fertility Dr. Sharda JainSecretary GeneralDelhi Gynaecologist ForumHOD, Puspanjali Crosslay Hospital
2 Reproductive organs Ovary Uterus Passive organ Responds to endogenous or exogenous hormones for everNo senescenceActive organ with fixed deposit of oogonia at birthOnce fixed deposit is over no response to endogenous or exogenous hormonesmenopause
3 Why ovarian ageing? Birth: 1-2 million oogonia Puberty: 3 to 5 lac oogoniamenopause: Follicular exhaustion(number of resting follicles below 1000)ovulation atresia3-5 lacIn healthy woman accelerated loss & accelerated qualitative decline of follicles start at 37.5 years when only resting follicles remain in ovaries. Fertility , both natural and assisted, declines rapidly after 37.5 years and almost becomes zero at age 41.
4 DIAGNOSIS OF POOR RESPONDERS RETROSPECTIVE TWO ATTEMPS OF COH IN SUPEROVULATION PROTOCOLS<3 DOMINANT FOLLICLESE2 LEVELS OF < 1000 PG/ML.
5 PROFILE OF POOR RESPONDER age> 35yrsUnexplained infertilityClinical history consistent with previous ovarian damagePrior cycle cancellation due to poor responseWomen nearing end of reproductive life and having menstrual problems
6 Other causes of premature ovarian ageing (poor responder)? H/o Early menaupause (F/H)SmokingPelvic inflammatory diseaseEndometriosisChemotherapyPelvic surgery and not just ovarian surgeryHIV and hepatitisProlonged use of ocp! myth?
7 Types of Tests to Predict Ovarian Ageing CHRONOLOGICAL AGEENDOCRINE TESTSBasal FSH, E2, FSH:LH ratio, Inhibin B and AMH levelsULTRA-SONOGRAPHYOvarian volume and AFCDYNAMIC TESTSCCCTGASTEFORTINVASIVE TESTS
8 AGE↓ NO. OF OOGONIA & DECLINE IN OOCYTE QUALITYTietze & Hutterite: women in Canada and USA:11% cease having children at 34 years, 33% no pregnancies after 39years and extremely rare pregnancy after 45 yearsPOOR IMPLANTATION AND ↑ CHANCES OF ABORTIONVirro etal.,1984;HIGHER RISK OF GENETIC ABERRATIONS:Lim AST , Fertil Steril 1997: rate of genetic aberration 24% in < 34 years, 52% b/w and 95.8% in age > 40 years
9 D3 FSH ↑10 IU/L are considered ABNORMAL BASAL FSHD3 FSH ↑10 IU/L are considered ABNORMAL- Correlates with fewer available oocytes- Poor outcome with IVFNo statistical variation in predictive value of D2 to D5 FSH in regular cyclesFluctuating FSH values indicates poor ovarian reserve
10 BASAL FSH LARGEST RETROSPECTIVE STUDY OF 758 IVF CYCLES FSH < 15 miu/ml- PR 17%,FSH : PR 9.3%FSH> 25 : PR 3.6%Scott RT , Fertil Steril 1995
11 D3 Estradiol: > 60 pg/ml BASAL E2D3 Estradiol: > 60 pg/mlDifficulty in achieving pregnancyCharacterstic of years preceding menopauseBENEFICIAL IN SCREENING FOR POTENTIAL POOR OVARIAN RESPONDER IN CASES WITH NORMAL FSH VALUE
12 ↓ false negative results BASAL E2DAY3 E2 CAN VARY AS MUCH AS 40% WHERE AS D2 TO 4 FSH SHOWS ONLY 18% VARIANCEEARLY PREDICTION COMPARED TO BASAL FSHFSH & E2 (combined)-↓ false negative results
13 BASAL E2 ≥ 60 pg/ml Liccardi etal , Fertil Steril 1995 NO PREGNANCY with basal E2 >75, Maximum pregnancy with E2< 30Smotrich etal , Fertil Steril 1995,No Pregnancy with E2>100,lower PR ,↑cancellation with E2 > 80≥ 60 pg/ml
14 FSH: LHFSH: LH> 3 despite normal FSH values may help to identify poor ovarian responderFewer oocytes retrieved, lower implantation rates, poor clinical PRBarroso G etal 2001;LH / FSH ≥ 2 / PCOS
15 HIGH LH>10 MIU/ML:INDICATESPOOR RESPONSE PCOD- IR
16 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.,2000Follicles of obese women produce less inhibin B as compared to lean womenLow inter-cycle variation compared to FSH≤ 45 pg/ml
17 ANTI MULLERIAN HORMONE (AMH) AMH is produced by granulosa cells of small antral follicle till they become sensitive to FSHAMH disappears at menopause or after oopherectomyAMH levels of less than 1.1 associated with IVF failureANTRAL COUNT
18 ULTRA-SONOGRAPHYOvarian volume is an independent predictor of IVF outcome (N-7 cc)Volume <3 cc-predicted 50% cancellation rateAntral Follicle Count:<5 in no- inactive ovaries5-10 in no: normal>15: PCO
20 DYNAMIC TESTS OF OVARIAN RESERVE Clomiphene Citrate challenge test (CCCT)Gonadotropin agonist stimulation test (GAST)Exogenous FSH ovarian reserve test (EFORT)No test absolutePoor prognosisHelps in decision making process.
21 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 1987Assesses ovarian reserve in women with intact HPO axis94% accurate and beneficial in unexplained infertility2-3 times better pick up rate than basal FSH. Recent meta-analysis shows CCCT equal to basal FSH as predictor.Jain et al 2004
22 CLOMIPHENE CITRATE CHALLENGE TEST (CCCT) Prevalence of abnormal test – 10%↑ with - ↑ age↑ ↑ - unexplained infertilityNormal Day 3 FSH & ↑ Day 10 FSH – same poor results as of ↑ Day 3 FSH≥15-17 MIU/ML ON Day 10Poor Prognosis - PAI
23 GnRH AGONIST STIMULATION TEST (GAST) Evaluates change in serum E2 between D2 and D3 after s/c administration of 1 mg of Leuprolide acetateE2 elevation by D2 and decline by D3 had better implantation and PRNo rise or persistent elevation : poor implantation and pregnancy ratePadilla etal
24 EXOGENOUS FSH OVARIAN RESERVE TEST (EFORT) E2 level is assessed on D3 and then 24 hrs after administration of 300 IU of purified FSHIncrease in E2> = 30pg/ml predictive of good response in subsequent IVF cycle
25 HOW TO TREAT POOR RESPONDER? Ovulation inductionCC followed /overlap with HMGHigh dose HMG (4 to 6 amp/day) from day 2-3GnRH agonist with HMGShort protocolFlare up protocolMini dose GnRH agonist for long protocoldown regulationAntagonist protocol
26 ADDITIVES TO IMPROVE RESPONSE Growth hormoneGH releasing factor
27 CONCLUSIONSIDEALLYFSH SHOULD <10MIULH <8MIUE2 <5O PG
29 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.
30 E2 LEVEL >60 PG/MLIT INDICATES FOLLICLE FUNCTIONING AT ACCELERATED LEVELS AND THESE CYCLES OFTEN YIELD OOCYTES OF REDUCED QUALITY.