1. Low AMH-
Is it related to Infertility?
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
M Sc, Sexual and Reproductive Medicine (South Wales, UK)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
Managing Committee Member, BOGS, 2022-23
Executive Committee Member, ISAR Bengal, 2022-24
Clinical Examiner, MRCOG Part 3 Examination
Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London, 2019

2. Declining ovarian reserve is THE RULE

3. Declining ovarian reserve is THE RULE

4. Terminology
1. Ovarian Reserve- Quantity and quality of
remaining oocytes present in both the ovaries
at a given age
2. Ovarian Responsiveness- Number of oocytes
developed/ retrieved after COH
3. Ovarian Ageing- Decline in quantity and
quality of ovarian activity because of
individualized rhythm of the “biological
clock”

5. Ovarian Reserve Tests
Commonly Used
• Age
• AMH
• AFC
• FSH
Others
• Inhibin B
• Ovarian Volume
• Ovarian blood flow
(Doppler)
• Dynamic Tests

6. Female Age-
Most valuable parameter

7. Day3 FSH
FSH >15 IU/L
+
Estradiol >75 pg/ml
(>200 pmol/L)
• Cycle dependent
• Inter-cycle variation
• Single abnormal FSH-
not reliable <40 yr of
age

8. Antral Follicle Count (AFC)
• Day 2-4
• TVS- 2-9 mm follicles
• Direct measure of
cohort of follicles
capable of responding to
the stimulation
• Observer and machine
dependent
• 3-D manual and sono-
AVC- ?
• Problematic in presence
of ovarian mass

9. Anti-Műllerian Hormone (AMH)
• Secreted by granulosa cells
• Paracrine control, independent
of HPO endocrine feedback
• Correlates with AFC, FSH,
Inhibin B, E2
• Higher sensitivity and
specificity than conventional
markers
• Declines earlier than FSH
rise

10. Primordial
Follicle
Small
Preantral
Large
Preantral
Small
Antral
(2-7 mm)
Large
Antral
(8-12 mm) Preovulatory
Atresia
Atresia Atresia
AMH
FSH
70-80
days Last 20
days
Initial Recruitment Cycle Recruitment Selection
Dominance
Paracrine Control
(Gn Independent)
Endocrine Control
(Gn Dependent)
Estrogen

11. Role of AMH in Ovarian Dynamics
• Prevention of unnecessary and excessive
recruitment of primordial follicles
• Restriction of follicular sensitivity to FSH
• Follicular Preservation
• Indirectly helping mono-follicular
development

12. Variability of AMH
La Marca A, Grisendi V, Griesinger G. How Much Does AMH Really Vary in
Normal Women? Int J Endocrinol. 2013;2013:959487.

13. Intra-Class Coefficient (ICC)
Fanchin R, Taieb J, Lozano DH, Ducot B, Frydman, R, Bouyer J. High reproducibility of serum
anti-Mullerian hormone measurements suggests a multistaged follicular secretion and
strengthens its role in the assessment of ovarian follicular status. Hum Reprod 2005; 20(4): 923–7.

14. Factors affecting AMH

15. Reproductive and lifestyle factors
affecting AMH
• Direct association of
low AMH
1. Increasing age
2. Short cycles/
Amenorrhea
3. Family history of POF.
• No correlation with
1. Smoking
2. Sleep
3. Diet
4. BMI
5. Sedentary lifestyle
6. Cell phone or laptop use
Banerjee K, Thind A, Bhatnagar N, Singla B, Agria K, Bajaj P, Jindal A, Arora S,
Goyal P, Mittal B, Malhotra K, Pai H, Malhotra J, Goel P, Jindal N. Effect of
Reproductive and Lifestyle Factors on Anti-Mullerian Hormone Levels in Women of
Indian Origin. J Hum Reprod Sci. 2022 Jul-Sep;15(3):259-271.

16. How “low” is “low”?
• No unanimous consensus
Alipour, F.G., Rasekhjahromi, A., Maalhagh, M., Sobhanian, S., & Hosseinpoor, M.
Comparison of Specificity and Sensitivity of AMH and FSH in Diagnosis of
Premature Ovarian Failure. Disease Markers, 2015;2015:585604.

17. Doroftei B, Mambet C, Zlei M. It's Never over until It's over: How Can Age and
Ovarian Reserve Be Mathematically Bound through the Measurement of Serum AMH-
A Study of 5069 Romanian Women. PLoS One. 2015 Apr 24;10(4):e0125216.

18. Rate of decline in AMH
Age (year) Mean
decline
Median
decline
Standard deviation
decline
<30 0.3
ng/ml/year
0.25
ng/ml/year
0.15
ng/ml/year
31-35 0.2
ng/ml/year
0.2
ng/ml/year
0.15
ng/ml/year
>36 0.1
ng/ml/year
0.1
ng/ml/year
0.1
ng/ml/year
Doroftei B, Mambet C, Zlei M. It's Never over until It's over: How Can Age and
Ovarian Reserve Be Mathematically Bound through the Measurement of Serum AMH-
A Study of 5069 Romanian Women. PLoS One. 2015 Apr 24;10(4):e0125216.

19. Discordance between ovarian
reserve tests
• Approximately 1/5
patients in clinical
practice had discordance
in their AFCs and AMH
levels (Zhang et al., Reprod Bio
Online, 2019)
• Laboratory vs Machine?
• Intermediate prognosis

20. AMH is assay-dependent
Li HWR, Robertson DM, Burns C, Ledger WL. Challenges in Measuring AMH
in the Clinical Setting. Front Endocrinol (Lausanne). 2021 May 24;12:691432.

21. AFC vs AMH
• The faster decline in AMH than in AFC with
age
• The reproducibility for AMH seemed much
better than for AFC.
Arvis P, Rongières C, Pirrello O, Lehert P. Reliability of AMH and AFC
measurements and their correlation: a large multicenter study. J Assist
Reprod Genet. 2022 May;39(5):1045-1053.

22. AMH vs AFC-
Evidence from Endometrioma Surgery
Younis JS, Shapso N, Ben-Sira Y, Nelson SM, Izhaki I. Endometrioma surgery-a
systematic review and meta-analysis of the effect on antral follicle count and anti-
Müllerian hormone. Am J Obstet Gynecol. 2022 Jan;226(1):33-51.e7.

23. Zhang Y, Xu Y, Xue Q, Shang J, Yang X, Shan X, Kuai Y, Wang S, Zeng C. Discordance
between antral follicle counts and anti-Müllerian hormone levels in women undergoing in
vitro fertilization. Reprod Biol Endocrinol. 2019 Jul 4;17(1):51.
AFC AMH Cycle cancellation
rate
Clinical pregnancy rate
Group A ≥7 ≥1.1 ng/ml 33.88% 43.32%
Group B ≥7 <1 ng/ml 32.94% 43.86%
Group C <7 ≥1.1 ng/ml 46.61% 23.81%
Group D <7 <1 ng/ml 68.73% 25%
AFC better than AMH for predicting POR

24. Ovarian Reserve
Quantitative
• Poor response to COH
Qualitative
• No test can predict
• Age

25. Qualitative Ovarian Reserve

26. Age and Euploidy
Capalbo A et al.. Hum Reprod Update 2017; 23:706–722.

27. Does low AMH mean infertility?
• Prospective, time-to-pregnancy cohort study of
women (N=981) 30–44 years, trying to
conceive for ≤3 months
• Raleigh-Durham area, North Carolina
Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, Baird
DD. Association Between Biomarkers of Ovarian Reserve and Infertility Among Older
Women of Reproductive Age. JAMA. 2017 Oct 10;318(14):1367-1376.

28. AMH is NOT the marker for “natural fertility”
Steiner AZ, Pritchard D, Stanczyk FZ, Kesner JS, Meadows JW, Herring AH, Baird DD.
Association Between Biomarkers of Ovarian Reserve and Infertility Among Older Women of
Reproductive Age. JAMA. 2017 Oct 10;318(14):1367-1376.

29. 41 yr, undetectable AMH !!!
Fraisse T, Ibecheole V, Streuli I, Bischof P, de Ziegler D. Undetectable serum anti-Müllerian
hormone levels and occurrence of ongoing pregnancy. Fertil Steril. 2008 Mar;89(3):723.e9-11

30. Low AMH ≠ Donor oocyte
• The predictive accuracy of AMH for 1-year
CLBR in GnRH antagonist treatment cycles
was limited and did NOT yield much
additional value on top of age.
• Withholding treatment based on predictors
such as age, AMH, or combination, remains
problematic.
Hamdine O, Eijkemans MJ, Lentjes EW, Torrance HL, Macklon NS, Fauser BC, Broekmans FJ.
Antimüllerian hormone: Prediction of cumulative live birth in gonadotropin-releasing hormone
antagonist treatment for in vitro fertilization. Fertil Steril 2015; 104: 891–8.

31. Predictive power of AMH
• Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P,
Eijkemans MJ, Mol BW, Broekmans FJ; IMPORT study group. Added value of
ovarian reserve testing on patient characteristics in the prediction of ovarian
response and ongoing pregnancy: an individual patient data approach. Hum Reprod
Update. 2013 Jan-Feb;19(1):26-36.

32. AMH can predict ovarian
response

33. IVF is stressful for Fertility Physicians

34. Low AMH in younger women
• Retrospective cohort study
• Only patients <38 years old at time oocyte
retrieval
• Patients with AMH values in bottom 10th
%tile were compared to patients in the IQR
(25–75th %tile).
Morin SJ, Patounakis G, Juneau CR, Neal SA, Scott RT, Seli E. Diminished ovarian
reserve and poor response to stimulation in patients <38 years old: a quantitative but
not qualitative reduction in performance. Hum Reprod. 2018 Aug 1;33(8):1489-1498.

35. Morin SJ, Patounakis G, Juneau CR, Neal SA, Scott RT, Seli E. Diminished ovarian
reserve and poor response to stimulation in patients <38 years old: a quantitative but
not qualitative reduction in performance. Hum Reprod. 2018 Aug 1;33(8):1489-1498.

36. Low AMH in older women
• Retrospectively analysed
• Women aged >36 years
• Divided into two groups:
1. AMH high (= > 1.1 ng/ml, H)
2. AMH low (< 1.1 ng/ml, L)
Dai X, Wang Y, Yang H, Gao T, Yu C, Cao F, Xia X, Wu J, Zhou X, Chen L. AMH
has no role in predicting oocyte quality in women with advanced age undergoing
IVF/ICSI cycles. Sci Rep. 2020 Nov 12;10(1):19750.

37. Age rather than AMH affects the quality
of oocytes in older women
Dai X, Wang Y, Yang H, Gao T, Yu C, Cao F, Xia X, Wu J, Zhou X, Chen L. AMH
has no role in predicting oocyte quality in women with advanced age undergoing
IVF/ICSI cycles. Sci Rep. 2020 Nov 12;10(1):19750.

38. Low AMH- Young vs Older
• 296 infertile patients with AMH measured
• Younger group, aged 25-38 years
• Older group, aged 39-42 years
• AMH levels of <1.0ng/mL and ≥1.0ng/mL
were compared.
• Young women with low AMH- good
prognosis if blastocyst can be developed
Miyagi M, Mekaru K, Nakamura R, Oishi S, Akamine K, Heshiki C, Aoki Y. Live birth
outcomes from IVF treatments in younger patients with low AMH. JBRAAssist
Reprod. 2021 Jul 21;25(3):417-421.

39. AMH is a predictor of live birth among
older, but not younger, women
Miyagi M, Mekaru K, Nakamura R, Oishi S, Akamine K, Heshiki C, Aoki Y. Live birth
outcomes from IVF treatments in younger patients with low AMH. JBRAAssist
Reprod. 2021 Jul 21;25(3):417-421.

40. Defining Poor Responders

42. • A young woman with a poor response >>>
older woman with a poor response
Poor Responders ≠ Same
Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis
always poor?: a systematic review. Hum Reprod Update. 2012 Jan-Feb;18(1):1-11. doi:
10.1093/humupd/dmr037. Epub 2011 Oct 10. PMID: 21987525.

43. ESHRE Bologna: One size does
NOT fit for all

44. Poseidon (Patient-Oriented Strategies
Encompassing IndividualizeD Oocyte Number)

45. Front.
Endocrinol.
10:387.
doi:
10.3389/fendo.2019.00387
POSEIDON

46. Young women Older women
Good Ovarian
Reserve
Group 1 Group 2
Poor Ovarian
Reserve
Group 3 Group 4

47. Good Ovarian
Reserve
Group 1 Group 2
Poor Ovarian
Reserve
Group 3 Group 4
Unexpected poor
response
Expected poor
response
•Asynchrony
•Gn Receptor gene
polymorphism
•Low dose Gn (like high BMI)
•Less potent Gn
•Unexplained
•Ovarian aging
•Ovarian insult (surgery)
•Genetic (Karyo, FMR1)

48. Young women Older women
Good Ovarian
Reserve
Group 1 Group 2
Poor Ovarian
Reserve
Group 3 Group 4
Low risk of
Aneuploidy
High risk of
Aneuploidy

49. CLBR depends on POSEIDON group

50. Stimulation regimes for POR
High dose Gn No benefits >300 IU FSH
GnRH Agonist protocols
Long protocol Oversuppression
Short protocol (Flare-up) Theoretically less suppression
Microdose flare up protocol Cost-friendly
Ultra-short protocol Not much benefit
Cessation/ Stop protocol No additional advantage
GnRH Antagonist protocols
Flexible vs fixed protocol Most widely used
GnRH Agonist-antagonist protocol Not much benefit
Natural cycle Not recommended
Modified natural cycle Not recommended
Mild stimulation protocol
CC/ letrozole + Gn + Antag No additional benefit
Luteal phase stimulation No additional benefit
Dual stimulation Needs further studies

51. Does low AMH mean increased
risk of pregnancy loss?

52. Serum AMH- a marker of RPL?
• RPL patients demonstrated AMH levels
significantly lower than the normal population,
both in women aged ≤35 years (p<0.004), and
those aged >35 years (p>0.03).
Catherine D. McCormack, Shalem Y. Leemaqz, Denise L. Furness, Gustaaf A.
Dekker & Claire T. Roberts (2019) Anti-Müllerian hormone levels in recurrent
embryonic miscarriage patients are frequently abnormal, and may affect
pregnancy outcomes, Journal of Obstetrics and Gynaecology, 39:5, 623-627

53. Low AMH does NOT increase risk of
pregnancy loss after IVF-ICSI
• Retrospective cohort
study on 1383 women
undergoing their first
IVF/ICSI cycle in
Finland
Peuranpää P, Hautamäki H, Halttunen-Nieminen M, Hydén-Granskog C, Tiitinen
A. Low anti-Müllerian hormone level is not a risk factor for early pregnancy loss
in IVF/ICSI treatment. Hum Reprod. 2020 Mar 27;35(3):504-515.

54. Low AMH was associated with embryo
aneuploidy ONLY ≥35 years age
• Retrospective study of 422 IVF cycles of 394 unexplained
RPL patients undergoing PGT-A,
• Divided on AMH levels
1. Group 1: low AMH <1.50 ng/ml
2. Group 2: normal AMH 1.50– < 5.60 ng/ml
3. Group 3: high AMH ≥ 5.60 ng/ml
• Aneuploidy was significantly higher in the low AMH group
compared with that in the normal AMH group (P1vs2 = 0.002)
and high AMH group (P1vs3 = 0.015).
• After age stratification, embryonic aneuploidy rate was still
significantly different among AMH groups with a similar trend
in women ≥35 years old (P1vs2 = 0.025, P1vs3 = 0.035), but not
in young subjects
Jiang X, Yan J, Sheng Y, Sun M, Cui L, Chen ZJ. Low anti-Müllerian hormone
concentration is associated with increased risk of embryonic aneuploidy in women
of advanced age. Reprod Biomed Online. 2018 Aug;37(2):178-183.

55. Why we should NOT ignore
low AMH?

56. AMH- earlier predictor of POF
AMH Day3 FSH
Sensitivity 80% 29%
Specificity 79% 79%
PPV 17% 17%
NPV 99% 87%
Diagnostic
accuracy
79% 72%
Alipour, F.G., Rasekhjahromi, A., Maalhagh, M., Sobhanian, S., & Hosseinpoor, M.
Comparison of Specificity and Sensitivity of AMH and FSH in Diagnosis of
Premature Ovarian Failure. Disease Markers, 2015;2015:585604.

57. AMH is highly predictive for timing of menopause
Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A, Themmen AP, Laven JS, de
Jong FH, Te Velde ER, Fauser BC, Broekmans FJ. Anti-mullerian hormone predicts
menopause: a long-term follow-up study in normoovulatory women. J Clin Endocrinol Metab.
2011 Aug;96(8):2532-9

58. Fixed interval hypothesis
Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and
clinical consequences. Endocr Rev. 2009 Aug;30(5):465-93.

59. AMH can help in decision
taking

60. See the overall scenario
• Age
• Duration of trying for pregnancy
• Previous treatment received
• Tubal factor
• Male factor
• Other pathologies- endometriosis, fibroid,
hydrosalpinx etc
• What the couple wants

61. Low AMH and ………..
Tube block in HSG
• IVF rather than
laparoscopy
Tube, semen normal
• Unexplained
subfertility
(ASRM, 2020)
Male factor
• Not to do repeated IUI
cycles

62. Try differently than before

63. Endometriosis- the biggest confusion
• In endometriosis, with
and without a history of
ovarian surgery, ovarian
reserve markers were
worse (lower AMH and
higher FSH) compared to
women with male factors
Romanski PA, Brady PC, Farland LV, Thomas AM, Hornstein MD. The effect of
endometriosis on the antimüllerian hormone level in the infertile population. J
Assist Reprod Genet. 2019 Jun;36(6):1179-1184.

64. Endometrioma-related reduction in
ovarian reserve (ERROR)
Kasapoglu I, Ata B, Uyaniklar O, Seyhan A, Orhan A, Yildiz Oguz S, Uncu G.
Endometrioma-related reduction in ovarian reserve (ERROR): a prospective longitudinal
study. Fertil Steril. 2018 Jul 1;110(1):122-127.

65. Endometriosis- surgery or not
Yılmaz Hanege B, Güler Çekıç S, Ata B. Endometrioma and ovarian reserve: effects of
endometriomata per se and its surgical treatment on the ovarian reserve. Facts Views
Vis Obgyn. 2019 Jun;11(2):151-157.

66. Role of adjuvants

67. • In women identified as poor responders
undergoing ART, pre-treatment with DHEA or
testosterone may be associated with improved
live birth rates.
• The overall quality of the evidence is moderate.
• There is insufficient evidence to draw any
conclusions about the safety of either androgen.
• Definitive conclusions regarding the clinical role
of either androgen awaits evidence from further
well-designed studies.
Role of DHEA
Nagels HE, Rishworth JR, Siristatidis CS, Kroon B. Androgens
(dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.
Cochrane Database Syst Rev. 2015 Nov 26;(11):CD009749

68. •Consider
DHEA/ Testosterone/
GH

70. Unanswered questions?
• ICSI for all ?
• Ideal day of transfer-
D3/D5?
• PGT for all?
• Oocyte pooling and
embryo banking?
• In vitro activation of
oocytes (IVA)
• Mitochondrial transfer
• Intraovarian PRP

71. Social egg freezing-
race against time?
• Often perceived (and
promoted) as a form
of insurance
• Success rates will be
limited in women
who are already in
their mid–late 30s
• Significant costs
• Low fecundity rate

72. Donor oocyte
• Repeated IVF failure
• High FSH and low AMH
( how high is high and how low is low)
• Counselling

73. Conclusion
• AMH predicts ovarian response
• AMH can help in decision making
• AMH cannot predict egg quality, pregnancy, live birth
• Low AMH ≠ Egg donation
• Low AMH ≠ IVF
• See the overall scenario
• Can offer adjuvant (DHEA) but do NOT delay active
treatment
• Best stimulation protocol?
• Unconventional protocols in IVF need further studies
• Overall prognosis may be guarded for low AMH + age
>35

74. AMH is a number