How does one manage women with diminished ovarian reserve when they approach centres for infertility treatments? What options do providers of assisted reproductive technologies have in the above case? IVF? ICSI?

1. Dr. K. Anuradha,
F.R.C.O.G.
Diminished
ovarian
reserve
What
options
do we
have

2. Infertility is a significant medical concern
• With the evolution of assisted reproductive
technologies the no. of couples seeking
evaluation and treatment for infertility has
increased

3. Infertility is a significant medical concern
• Infertility services may range simple medical
advice to IVF, but the backbone of modern
fertility assessment of infertile couple
begins with thorough history and physical
exam
• Additional radiologic and laboratory evaluations can
direct management and predict potential response
to infertility treatment

5. Maternal age
Ovarian reserve
Diagnosis &
Past reproductive
performance
Primary prognostic
indicators for success

6. Refers to the quantity
and quality of residual
ovarian follicular pool
Reflects woman’s
reproductive potential
and ART outcome
What is Ovarian reserve

7. The most common diagnosis of
female infertility in those
undergoing ART –
‘diminished ovarian reserve’
(According to Assisted reproductive technology
National summary report, 2015)

8. Diminished Ovarian reserve - DOR
• Decrease in the quantitiy & quality of oocytes
• Describes women of reproductive age with
regular cycles mostly ovulatory whose
response to stimulation & fecundity is
reduced compared to women of
comparable age
DOR is irreversible, and are at risk of poor
response to ovarian stimulation
DOR is a poor prognostic factor in ART

9. Total no. of oocytes in any given women is
* Genetically determined &
* Inexorably declines through out life
‘Natural’ age-related decline
DOR -Etiology
DOR – Incidence
approximately 10 % of infertile women

10. Maternal Age
• One of the most important factor in
determining the likelihood of success
• Age related decline in biologic fertility,
Can not be reversed or negated
At birth – 1-2 million
Puberty – 30,000
40 yrs – 25,000
Menopause - < 1,000
The rate of follicular depletion
Not constant
Increases as no. of follicles remaining decreases

11. Age –Live Birth Rate
• Pattern reflects progressive decline in
–Response to ov. Stimulation
–Fewer oocytes, embryos &
–Reduced implantation rates
Due to declining oocyte quality

12. Maternal age – LBR in ART
• < 35 yrs – 39.6%
• 35–37 yrs – 30.5%
• 38–40 yrs – 20.9%
• 41-42 yrs – 11.55%
• 43-44 yrs – 5.4%

13. Maternal age – Miscarriage rate in IVF
Age dependent decrease in
SR related to-increasing
prevalence of aneuploidy
in aging oocytes
– Reflected in incidence
of miscarriage
– < 35 yrs - <14%
– 38 yrs – 19%
– 40 yrs – 28%
– >44 yrs – 60%

14. PAO
Normal Decline 25000
Accelerated
Decline
Early
Menopause
• 37 – 38 yrs –
25,000 follicles
• 51 yrs –
menopause, 1000
follicles
Accelerated
decline in
fertility at
age
• Approx
13.5yrs
Time period
between
accelrated
decline in fertility
is fixed at
Normal Decline
25000
Accelerated
Decline
Early
Menopause

15. DOR - Etiology
• Certain pelvic infections
• Endometrioma
(damage caused to ov.
Follicles)
– Surgical excision
– Mechanical pressure on
ov.cortex
– Impaired vascular network
• Iatrogenic
– Ovarian surgery
– Tubal surgery
– Uterine artery ligation LOD
• Little is known
• Affected by age, genetics &
environmental factor
– Idiopathic
– Smoking
– Obesity
– Mumps
– Galactosaemia
– Autoimmune
– Radiotherapy/Chemotherapy
– Genetic mutations like FMRI
– Ethnicity –
(ov. Age of Indian women approx. 6
yrs. Older than spanish counter
parts)

16. DOR – FMRI gene mutation
Altered expression of certain genes
in cumulus & granulosa cells
* FSH receptor (FSHR)
polymorphism
* FMRI gene mutation
- 15-25% premature
menopause

17. Although the no. & quality of oocytes
decline with age, fertility varies
significantly among women of similar age
ORTS are aimed at identifying
individuals at risk for diminished
ovarian reserve
ORT

18. Ovarian reserve tests (ORT)
Intends to
• Predict fertility
• Provide prognostic information re-
likelihood of success

19. Basis for Ovarian reserve tests
Size of remaining follicular pool
Circulating inhibin-B levels
(from primary and small antral follicles)
Resulting in lower levels of Feed-back
inhibition &
A progressive increase in s.FSH levels
(most noticeably during early foll.phase)

20. • Increasing intercycle FSH
conc. Stimulates
– Early follicle recruitment
– Advanced follicle development
early in cycle
– Earlier rise in S.E2
– Shorter follicular phase
– Decreasing overall cycle
length
Physiology of
reproductive
aging
provides
foundation
for all
contemporary
tests for
ovarian
reserve

21. Ovarian reserve tests
Biochemical tests
• FSH
• Estradiol
• Inhibin-B
• AMH &
• Provocative tests
eg. CC challenge
test
Ultrasonographic
measurements
• AFC
• Ovarian volume
Measures the ‘size’ & ‘quality’ of ovarian
follicular pool

22. Basal FSH concentration
• Simplest and still most widely applied measure
• Rising FSH levels indicates reproductive aging
• Best obtained during early follicular phase (D2-4)
• FSH levels > 10 U/lit
‘High specificity’
(80 -100 %)
For predicting
‘poor response to
stimulation’
‘sensitivity’
(10-30 %)
Low & decreases
With threshold value

23. Interpreting FSH values
• Most women including those with DOR will have a
normal result
• FSH levels vary significantly
• Single elevated FSH conc. –
does not have high specificity
for predicting poor response to stimulation
or failure to achieve preg.
• Consistently high values are – associated with
poor prognosis
‘serial testing in efforts to select the ideal cycle
for treatment does not improve outcomes in
women with fluctuating FSH’

24. Basal serum E2
• Has a little value as an ORT
• Provides additional information that ‘helps
interpretation of FSH level’.

25. Interpretation of dual tests
(FSH/S.E2)
‘Early elevation of serum E2’ reflects –
-advanced follicular development & early selection of
dominant follicle (as classically observed in women of
advanced reproductive aging)
Will suppress FSH conc.
Masking an otherwise obviously high level indicating DOR
Basal FSH (N) & serum E2 (> 60 – 80 pg/ml)
Likelyhood of ‘poor response’
Ov.stimulation & chances of preg.
Both FSH &
E2
Ov. Response to stimulation is
likely to be ‘very poor’

26. Antimullerian hormone (AMH)
• Produced by granulosa cells of -
– Preantral and small antral follicles
– Beginning when primordial follicles start development &
– Ending when they reach a diam. Of 2-6mm.
• Small antral follicles –
Primary source and contains large no. of granulosa cells
• No. of small AF correlates with the size of the residual
follicular pool and
AMH levels decline progressively
Becoming undetectable near menopause
• ‘Gonadotrophin independent’ –
Vary little – with in and in between cycles

27. Measure of AMH
• A ‘low-AMH’ cut off points –
• 0.2 – 0.7 ng/ml
• Sensitivity of 40 – 97%
• Specificity of 78 – 92%

28. AMH – Clinical Implications
• Very promising screen test for DOR, but more useful in:
– General IVF population or
– In women at high risk of DOR
• AMH levels associated with:
– Poor response to ovarian stimulation
– oocyte yield, embryo quality and pregnancy rates
• ‘Good – specificity’ for poor response to ovarian
stimulation
• But have proven ‘neither sensitive nor specific’ for
predicting pregnancy

29. Antral follicle – count (AFC)
Basics:
Reproductive age women have an estimated 20 – 150
growing follicles in the ovaries at any one time
Only few are large enough to be imaged (> 2mm) by TVS.
• 2 mm. sized follicles are at a stage responsive to FSH
• No. of small AF in ovaries proportional to
no. of primordial follicles remaining
no. of primordial follicles decrease, no. of small AF decline

30. Interpreting AFC
• A low AFC – ‘high specificity’ for –
– Poor response to ov.stimulation &
– Treatment failure
– Makes is a useful test
• But, ‘low – sensitivity’ –
Limits its overall clinical utility

32. DOR-ORT
• Women with ≥ 2 of the criteria:
– S. FSH - > 10 IU/L
– S.E2 - > 80 pg/ml
– S. AMH - < 0.5 – 1.1 ng/ml
– AFC ≤ 5
• ‘These women should be encouraged to
conceive sooner due to their shorter
fertility window’
(on D2/D3 of cycle)

33. Combined tests of ovarian reserve
• Complicated formulas are generally not useful in
clinical practice
• An analysis combining AMH, Inhibin-B, AFC & ovarian
volume found that –
• Only AFC & AMH predicted response &
• Combination predicted outcome no better than the
individual tests

34. Discordant ORT: What matters most ?
• When counselling women before an initial attempt at IVF
– physician generally use a combination of AMH, FSH & AFC
– to select appropriate gonadotropin dose for stimulation and
anticipate potential oocyte yield
• When testing is concordant i.e;
FSH & AMH &
FSH & AMH
• When testing is discordant:
– Approx. 20% of women
– Counselling more complicated
Counselling is
straight forward

35. Should ORT be a routine
• ORT as a routine element of pre-treatment
evaluation for IVF planning
• ‘Most useful’ in women at high-risk for DOR –
• to correctly identify women with DOR
• In a low-prevalence population –
– Many women with normal OR may be
categorized as having DOR
(false - +ve result)

36. Whom to test
• Women delaying child-bearing:
• Young cancer patients planned to
treatment
‘Knowledge of OR would lead women to
modify their decisions or make alternate
decisions’.

37. Interpretation of ORT
• None of the current ORT, is an accurate
predictor of pregnancy in IVF cycle
• The tests are adequate for ‘predicting’
poor response’, which does have
prognostic value;
although not as much in young
women as in older women

38. Diminished ovarian reserve-
Poor ovarian response
• DOR; associated with
– Increased gonadotrophin requirements
– Lower oocyte yield
– Less embryos available for transfer & cryopreservation
– Increased risks of cycle cancellation
• Women with DOR & POR –
– Lower PR & higher pregnancy loss compared to age
matched controls with normal ovarian reserve
When counselling patients planning IVF;
• Predictors of both potential oocyte yield &
• Likelihood of live-birth are invaluable

39. Poor Ovarian Responders
• Women who respond suboptimally to
ov.stimulation with gonadotropins
• Despite advancements in ARTs, POR is still
considered to be one of the ‘most challenging
tasks’ in reproductive medicine
• Incidence –
– Range from 9-24%
– Significant proportion of women undergoing
stimulation
– Diminished probability of preg. Even after IVF

40. Poor Ovarian Responders-
classification systems
• PORs are a heterogenous population
• Age & Oocyte yield have-
A substantial effect on pregnancy prospects
• Classification systems proposed:
1) To identify women with low prognosis in ART
2) To help individualise treatments and
3) To get at least one enploid embryo for transfer in
each patient as a clear practical goal

41. Poseidon Concept

42. Strategies or interventions in
DOR/POR
• ‘No single intervention’ or certain protocol is accepted as an
effective method
• Multiple strategies suggested:
– Use of adjuvant supplements
– Various IVF protocols
– Accumulation of vitrified oocytes or embryos
– Oocyte donation
The optimal management remains an unsolved problem
• ‘The overriding concern that women with DOR have a limited life
span to conceive with their own eggs governs all aspects of
management’

43. Pathogenesis for PORs – Basis
for interventions
Androgen excess is shown to stimulate
1) Early stage of follicle growth
2) in no. of pre-antral and antral follicles
3) Increased intra-ov. Conc. Of androgens
Augments FSH receptor (FSHR)
Enhances responsiveness of ov. to FSH
Accumulation of
androgens in the
micromilieu of
primate ovary,
plays a critical
role in
1) Early
follicular
development
2) Granulosa
cell
proliferation

44. Pathogenesis of POR
Inadequate levels of endogenous androgens
associated with:
Ov. Sensitivity of FSH & PR after IVF
on the basis of this data
Hypothesised that increasing androgen conc.
In ov.micro milieu in POR
might lead to
No. & maturity of oocytes in IVF after ov.stimulation
Hence use of androgens & androgen modulatins agents
proposed

45. Adjuvant Therapies
1) Pretreatment with DHEA
2) Pretreatment with transdermal testosterone
3) Addition of aromatase inhibitors
4) Addition of treatment LH
5) Addition of HCG during ovarian stimulation
6) Co-treatment use of
– GH
– Melatonin,aspirin

46. • Transdermal testosterone
– 10 – 12.5mg/d starting from 5-21 days in the
period preceeding ovarian stimulation
• Addition of aromatase inhibitors –
– 2.5 – 7.5 mg of Letrozole for 5 d from D3
– Inhibition of aromatase activity could
increase intraovarian androgen conc. By
blocking aromatization to estrogens
• Aspirin
– Good intra-ovarian blood flow is believed to
improve delivery of gonadotropic hormones
– Use of aspirin in IVF is debatable

47. • Addition of HCG
– To promote and complete the growth of large
follicles, in late stages of ovarian stimulation
– Addition of 75 – 100IU/d of HCG until
completion of ov.stimulation
• GH
– Modulates action of FSH on granulosa cells
by upregulating the local synthesis of
insulin-like growth factor – 1 (IGF-1)
– Lower cycle cancellation rates and reduced
dose of gonadotropins required in co-
treatment with GH

48. • COQ 10 – Mitochondrial Nutrient
• Melatonin
– A pineal gland hormone
– Regulates physiologic reproductive behaviour
and acts as free radical scavenger
– Supplementation has been used to improve
outcome of IVF cycles

49. Melatonin function
L
Luteal phase
‘Broad spectrum Antioxidant, suicidal Antioxidant’

50. Adjuvant supplements - DHEA
Currently used world-wide
• DHEA is an endogenous steroid-generated by the
adrenal glands & ovarian theca cells
Acts as a precursor of estradiol & testosterone
which is engaged in early follicular development
• DHEA supplementation – associated with increased
androgen concentration

51. Dosage DHEA

52. DHEA Benefits

53. DHEA’s beneficial effects on Fertility
• Increased quality & quantity of eggs & embryos
• Increased chances of spontaneous conceptions
• Shortened time to pregnancy
• Increased IVF pregnancy rates
• Decreased risk of miscarriage & chromosome
abnormalities in embryos
• Improved cumulative PRs in fertility
treatments

58. DHEA pretreatment in clinical
practice
DHEA supplementation most benefit in :
i) PORs with lower DHEA-S conc. (<180 μg/d1)
compared to those with higher DHEA-S
conc. ( ≥ 180 μg/d1)
ii) DOR associated with hypoandrogenism
Low androgen levels can be of
* Ovarian / adrenal androgen
DHEA-S is almost exclusively produced by
adrenals
DHEA-S reflects an adrenal cause for low
androgen levels

59. DHEA pretreatment in clinical
practice
• DHEA supplementation effective for
– Androgen deficiency of adrenal origin
– Secondary ov. Insufficiency induced by
adrenal hypoandrogenism
iii) In women with high AMH / low-
testosterone phenotype
associated with adrenal
insufficiency, DHEA equalizes
low to normal testosterone &
normalizes IVF cycle outcome

60. Preventing latrogenic DOR
• Avoiding unnecessary surgeries
– Surgery for endometriomas:-
Cystectomy –
» Significant decline in AMH levels
– LOD – markedly reduces AMH levels, in women with low or
normal AMH levels
– Salpingectomy –
» Not shown to compromise OR in the short term
• ‘Offering alternate therapies wherever indicated’,
• Young cancer patients:-
– Oocyte or embryo freezing prior to chemo/radiotherapy
• Social egg freezing – ‘race against time’
– Is it an insurance against age-related fertility decline

61. Oocyte donation - DOR
• May be the last efficient resort to offer
• OD most commonly performed in:
i) Women over age of 42
ii)Grossly abnormal ORT
iii)Whose IVF cycles
consistently yield
poor quality embryos

62. Oocyte donation - DOR
• Difficult decision for the couple –
Needs extensive counselling

63. Future for DOR
• Newer, Yet – to-be established approaches:
– Ovarian transplantation
– Mitochondrial transfer &
– Stem-cell based neo-oogenesis
• Attempts at isolating mitotic germ cells in
adult human ovaries

64. Future for DOR
• Development of artificial gametes from diploid
somatic cells
Needs further research to know realistic
paradigm of these approaches in DOR

65. • Bil. Ov. Endometriosis
• AMH – 2.39
• Lt.ov – 1-2 AF, Rt.ov – 2-3 AF

66. Is fragile X screening required ?

67. • 35 yrs
• AMH – 0.16
• FSH – 14.15
Would u consider stimulation ?

68. • 45 yrs
• FSH – 72.2
• LH – 39.2
• AMH – 0.01
What do you expect on
the scan ?
No AFC

69. • 31 yrs (2014)
• AMH – 0.01
What would be your
treatment option ?
• 36 yrs, AMH – 0.932
Ist IVF cycle – LP
6 OR, 4 F, 3ET
(Male child)

70. Conclusions
• DOR, poses a major challenge & is on the rising trend
• ORT:
– become a routine element of diagnostic evaluation
i) Abnormal tests help to
• Persuade older women ‘to abandon’ plans to
pursue aggressive, costly & likely futile
treatments
• Convince young women to do just the opposite
(to take fullest advantage of a rapidly closing
window of oppurtunity)

71. Conclusions
• Should be interpreted with caution
Rigid application of test results risks inappropriate
recommendations:
for treatment, or for no treatment
& both must be avoided
• Thorough patient counselling & protocol personalisation
are the keys to optimize reproductive outcome
• Women with DOR should be appropriately counselled to
undergo rather aggressive approach to achieve
pregnancy before it is too late
• Ultimately regardless of the prognosis, the SR for any
individual woman will be 0% or 100%

74. Dr. K. Anuradha,
F.R.C.O.G.