Clinical significance of diminished ovarian reserve. Presentation from the RHG Congress 2018.

1. Clinical significance of
diminished ovarian reserve
Richard A Anderson
Elsie Inglis Professor of Clinical Reproductive Science
University of Edinburgh

2. The ‘poor responder’
• What do we mean by this term?
• Is it reliable?
• What can we do about it?
• What might we be able to do about it?

3. Association between egg number
and live birth rate
Sunkara SK et al. Hum. Reprod. 2011;26:1768-1774
HFEA data: 400,000 cycles

4. The increasing gap between
women’s wishes and biology
0
5
10
15
20
25
<29 30-34 35-39 40-44 >45
Live birth
rate per ET
Templeton et al 1996 Lancet 384; 1402
0
50000
100000
150000
200000
250000
300000
<20 20-24 25-29 30-34 35-39 40-44 45+
1995
2005
OHE Compendium of Health Statistics

5. The variation as well as decline in
follicular endowment
Wallace and Kelsey 2010 PLoS One 5; e8772
Non-growing
follicle
number
Age

6. Wallace and Kelsey 2010 PLoS One 5; e8772
200/month
6.7 per day
22/month 2000/month
Calculation of
rate of follicle
activation

7. The long and hazardous road of follicle
development
From McGee and Hsueh 2000 Endocr Rev 21, 200
??? 120 Days
Primordial
Primary
Secondary
Antral
Human
(2 - 5mm)
Rat
(0.2 - 0.4mm)
Atretic
Pre-ovulatory
Follicles
OVULATION
SELECTION AND
DOMINANCE
CYCLIC
RECRUITMENT
INITIAL
RECRUITMENT
>30 Days 28 Days 2-3 Days
71 Days 14 Days
Human
Rat
Similar durations in Gougeon A 1986 Hum Reprod
On the radar

8. AMH and AFC reflect
primordial follicle number
Hansen et al 2010 Fertil Steril
Stereological analysis
following
oophorectomy, n=42
LogPrimordialfolliclenumber

9. R² = 0.6646
0
1
2
3
4
5
6
7
0 1 2 3 4 5 6
AMH(ng/ml)
Log NGF number
NGF vs AMH
R² = 0.600
1
10
100
20 30 40 50 60NGF/AMH
Age
NGF/AMH ratio vs age
Fewer antral follicles per NGF with age
Increased early selection?
The changing relationship between primordial
follicle number and AMH with age

10. Prediction of poor response
AUROC 95% CI
Age 0.60 0.57, 0.64
AMH 0.81 0.77, 0.84
Age, FSH 0.69 0.66, 0.72
Age, AFC 0.76 0.72, 0.80
Age, AMH 0.80 0.76, 0.84
Age, AMH, AFC 0.80 0.74, 0.86
Age, AMH, AFC, FSH 0.81 0.75, 0.0.86
IMPORT consortium Hum Repro Update 2013
EXPORT consortium Fertil Steril 2013
Biomarkers predict poor response

11. ‘Bologna’ criteria for poor response
• 2 of 3:
– Advanced maternal age or other risk factor
– Previous POR (≤3 oocytes)
– Abnormal ovarian reserve test
• Or 2 episodes of POR with max stimulation
• Reproducibility in a second cycle:
– 64% of ‘unexpected’ will show a normal response
– 31% of ‘expected’ will show a normal response
(n=225, Klinkert et al 2004)
Ferraretti AP et al; ESHRE working group on Poor Ovarian Response Definition 2011

12. 69% of DOR cycles did
not result in POR
0
5
10
15
20
2004 2011
DOR live birth
POR live birth
Devine K et al Fertil Steril 2015, 3, 612
Using ‘Diminished ovarian reserve’ to predict
poor ovarian response
Diminished ovarian reserve in the United States assisted reproductive technology
population: diagnostic trends among 181,536 cycles from the Society for Assisted Reproductive
Technology Clinic Outcomes Reporting System

13. Chai J, Lee VCY, Yeung TWY, Li RWH, Ho PC, et al. (2015) Live Birth and Cumulative Live Birth Rates in Expected Poor Ovarian Responders
Defined by the Bologna Criteria Following IVF/ICSI Treatment. PLoS ONE 10(3): e0119149.
Expected Normal (562) Expected Poor (160)
No of oocytes 11 (8-15) 5 (3-8)
Cancellations 0 1 (0.6%)
Live birth 202 (35.9%) 38 (23.8%)
Fresh plus frozen LBR 323/512 (62.8%) 48/134 (35.8%)
How well do predicted poor
responders do in IVF/ICSI?
1152 women undergoing first IVF/ICSI cycle (cutoffs: age 40, AFC 6, AMH 2ng/ml)

14. SART data by diagnosis
Luke et al 2012 NEJM 366, 2483

15. ROC analysis for AMH and successful egg retrieval in DOR patients (FSH>10IU/L)
Burks HR et al Fertil Sertil 2015, 3, 643
Can we do better?
Ultrasensitive AMH assay
No egg retrievals at <100pg/ml
n=24 /group

16. What else does having a poor ovarian
reserve mean?
From McGee and Hsueh 2000 Endocr Rev 21, 200
??? 120 Days
Primordial
Primary
Secondary
Antral
Human
(2 - 5mm)
Rat
(0.2 - 0.4mm)
Atretic
Pre-ovulatory
Follicles
OVULATION
SELECTION AND
DOMINANCE
CYCLIC
RECRUITMENT
INITIAL
RECRUITMENT
>30 Days 28 Days 2-3 Days
71 Days 14 Days
Human
Rat

17. Sowers, M. R. et al. J Clin Endocrinol Metab 2008;93:3478-3483
Prediction of menopause
50 women followed prospectively
(Michigan Bone Health and
Metabolism Study)
6 annual assessments
Mean initial age 42 yr
AMH signif related to both time to and
age at FMP
Inhibin B less predictive of both

18. AMH and prediction of menopause
Broer SL et al 2011 JCE&M
257 ovulatory women, 21-46yr
Reassessed after 11 years (19% menopausal)
AMH at baseline Menopause by AMH centileLow age specific AMH
Shift towards younger
age at menopause
High age specific
AMH
Shift towards higher
age at menopause

19. AMH and prediction of menopause
Tehrani et al 2013 JCE&M 98, 729

20. 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 1 2 3 4 5 6
Cumulativeproportionofwomen
achievingpregnancy
Time from cessation of birth control
(cycles)
0
10
20
30
40
50
60
70
19 21 23 25 27 29 31 33 35
AMH(pmol/L)
Age (years)
AMH and fecundability
Hagen et al 2012 Fertil Steril
AMH quintiles, middle 3 combined

21. 981 women aged 30 to 44, trying to conceived max 3 months at study entry Steiner AZ et al, 2017, JAMA
Adjusted for age,
smoking,
contraception, BMI,
race, prev
pregnancy

22. Changes in ovarian reserve after
chemotherapy
Identification of post-
cancer compromised
ovarian reserve?
Ovarianreserve

23. Effects of A(B)VD and BEACOPP on
ovarian function in Hodgkin lymphoma
0
5
10
15
20
Pre chemo 2 cycles EOT 1 2 3
AMH(pmol/L) AMH
Blue: ABVD
Red: BEACOPP
(after 2 cycles of ABVD)
Years after chemotherapy
Chemotherapy
Anderson RA et al 2018 Lancet Oncol

24. AMH and pregnancy after HL
0
2
4
6
8
10
12
Pre chemo 2 cycles EOT 1 2 3
AMH(pmol/l)
During pregnancy

25. Pre
C
ycle
1
C
ycle
2
C
ycle
3
C
ycle
4
C
ycle
5
C
ycle
6
0.0
0.5
1.0
1.5
2.0
2.5
**
**
*** ***
AMH(ng/ml)
AMH: application in childhood
cancer
Pre End Recovery
0
1
2
3
* **
AMH(ng/ml)
High risk
Pre End Recovery
0
1
2
3
**
AMH(ng/ml)
Medium/low risk
22 girls age 0.3-15yr
17 prepubertal
Brougham et al 2012 JCE&M 97, 2059

26. AMH in 3 girls with cancer
0 50 100 150 200
0.0
1.0
2.0
3.0
Age 2.4; rhabdomyosarcoma
0 25 50 75
0.0
0.2
0.4
0.6
0.8
1.0
Weeks
AMH(ng/ml)
Age 1.2; neuroblastoma
0 50 100 150
0.0
0.5
1.0
1.5
2.0
Weeks
Age 14.6: Hodgkin’s lymphoma
Brougham et al 2012 JCE&M 97, 2059
Can this predict their
reproductive lifespan?

27. Age and miscarriage
Maternal age
Percentmiscarrying
Nyboe Andersen et al 2000 BMJ 320, 1708

28. AMH and miscarriage after IVF?
Tarasconi et al Fertil Steril 2017, 108, 518
Age but not AMH predicted clinical pregnancy and live birth

29. AMH and miscarriage in natural
pregnancy?
Schumacker et al 2018 Fertil Steril 109, 1065Women (n = 533), age 30 - 44
Women with severely
diminished ovarian reserve (AMH < 0.4 ng/mL)
miscarried at over twice the rate of women
with an AMH > 1 ng/mL (HR 2.3; 1.3-4.3).

30. AMH and miscarriage in natural
pregnancy?
multivariable Cox model adjusting for
maternal age, race, obesity, and recurrent
pregnancy loss suggested that risk of
miscarriage showed a nonsignificant
trend to decrease with increasing AMH
(HR per unit increase in natural log of
AMH = 0.85; 0.72-1.01).
Schumacker et al 2018 Fertil Steril 109, 1065

31. Can we intervene to promote follicle
development?
From McGee and Hsueh 2000 Endocr Rev 21, 200
??? 120 Days
Primordial
Primary
Secondary
Antral
Human
(2 - 5mm)
Rat
(0.2 - 0.4mm)
Atretic
Pre-ovulatory
Follicles
OVULATION
SELECTION AND
DOMINANCE
CYCLIC
RECRUITMENT
INITIAL
RECRUITMENT
>30 Days 28 Days 2-3 Days
71 Days 14 Days
Human
Rat

32. Local and gonadotrophic regulation of
follicle growth
Scaramuzzi R et al 1993 Reprod Fertil Develop 5: 459-478
Local
FSH

33. Does giving more FSH help?
N=501 Standard 150 IU 225 or 450 IU
Oocytes retrieved 6.5 7.6
Cancelled first cycle 21% 7%
LBR first cycle 18% 18%
Cumulative LBR 44.8% 42.4%
van Tilborg et al 2017 Hum Reprod 32, 2496
OPTIMIST trial: predicted poor responders (AFC ≤7, 8-10)
Outcome: ongoing pregnancy/LB within 18 months

34. RECOMMENDATIONS
In patients who are classified as poor responders and pursuing
IVF, strong consideration should be given to a mild ovarian-
stimulation protocol (low-dose gonadotropins [≤150IU/d] with or
without oral agents) due to lower costs and comparable low
pregnancy rates compared with traditional IVF stimulation protocols.

35. Adding growth hormone?
N=130 rGH +FSH FSH only
LBR 11% 14%
Hart RJ et al Curr Opin Obstet Gynecol 2017
LIGHT study
rGH group had more egg recoveries and 1 day less ovarian stimulation
Recruitment stopped early
a benefit for the use of the adjunct GH, with a reduction in the duration of ovarian
stimulation required for oocyte retrieval, the collection of a greater number of oocytes
than placebo, and an improvement in many of the early clinical parameters; however,
there was no evidence of an increased chance of a live birth for the use of GH

36. Local and gonadotrophic regulation of
follicle growth
Scaramuzzi R et al 1993 Reprod Fertil Develop 5: 459-478
Local
Gns

37. By size
Vendola KA et al 1998 J Clin Invest 12, 2622
Androgens stimulate early follicular
growth in the primate
Rhesus monkey
Treated with T or DHT

38. DHEA pretreatment and LBR/ongoing
pregnancy
Nagels HE et al Cochrane Database Syst Rev. 2015:CD009749
OR 1.81, 95% CI 1.25 to 2.62
(8 RCTs, N = 878)

39. Testosterone pretreatment and LBR/ongoing
pregnancy
Nagels HE et al Cochrane Database Syst Rev. 2015:CD009749
OR 2.60, 95% CI 1.30 to 5.20
(four RCTs, N = 345)

40. Novel loci to impact follicle development
From McGee and Hsueh 2000 Endocr Rev 21, 200
??? 120 Days
Primordial
Primary
Secondary
Antral
Human
(2 - 5mm)
Rat
(0.2 - 0.4mm)
Atretic
Pre-ovulatory
Follicles
OVULATION
SELECTION AND
DOMINANCE
CYCLIC
RECRUITMENT
INITIAL
RECRUITMENT
>30 Days 28 Days 2-3 Days
71 Days 14 Days
Human
Rat
AMH
Regulation of
growth activation
 sensitivity to
FSH/selection

41. Campbell BK et al. Endocrinology 2012;153:4533-4543
Immunisation against AMH
promotes follicle progression
in sheep
Intraovarian AMH antibody increases the number of
antral follicles at midcycle
and primates
Xu J et al. Hum. Reprod. 2016;31:1522-1530
Control +AMH antibody

42. Conclusions
• Diminished ovarian reserve is common but we
aren’t very good at predicting poor response
• But still has acceptable outcomes in younger
women
• Can we improve response and outcomes?
– Yes, but effect size and safety/risks unclear
– Improved understanding of ovarian function
will allow new developments