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

2. 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

3. Why ovarian ageing? Birth: 1-2 million oogonia
Puberty: 3 to 5 lac oogonia
menopause: Follicular exhaustion
(number of resting follicles below 1000)
ovulation atresia3-5 lac
In 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 FOLLICLES
E2 LEVELS OF < 1000 PG/ML.

5. 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

6. 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?

7. 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

8. 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 and 95.8% in age > 40 years

9. 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

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 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

12. ↓ 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

13. 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

14. 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

15. HIGH LH
>10 MIU/ML:
INDICATES
POOR 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.,2000
Follicles of obese women produce less inhibin B as compared to lean women
Low 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 FSH
AMH disappears at menopause or after oopherectomy
AMH levels of less than 1.1 associated with IVF failure
ANTRAL COUNT

18. 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

19. INVASIVE TEST
OVARIAN BIOPSY
FOR FOLLICLE
CONCENTRATION

20. 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.

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 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

22. 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

23. 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

24. 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

25. 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

26. ADDITIVES TO IMPROVE RESPONSE
Growth hormone
GH releasing factor

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

28. CONCLUSIONS
FSH >20 MIU
NO HOPE WITH
DRUGS

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/ML
IT INDICATES FOLLICLE FUNCTIONING AT ACCELERATED LEVELS AND THESE CYCLES OFTEN YIELD OOCYTES OF REDUCED QUALITY.

31. 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

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

33. 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

34. thank you