How to optimize the outcome in infertile females with diminished ovarian reserve!

2. By A . P r o f e s s o r O f O b G y n , A l e x a n d r i a
Dr. Sherif Anis Hibisha
Managing Poor
Responders: How Late
is Too Late

3. Definition
Magnitude of the problem
Suggested etiology/ mechanism/ Genetic background
How to predict
Management options

5. the number of mature follicles on the day of human
chorionic gonadotropin (HCG) administration (<2 to <5), the
number of oocytes retrieved (<4 to <6), the serum estradiol
concentrations (<100 pg/mL on day 5 of stimulation or <300
to <600 pg/mL on the day of HCG), or the total gonadotropin
dose used and/or the daily stimulation dose and/ or
prolonged duration of gonadotropin stimulation

8. (Ferraretti et al. Eshre Consensus, 2011)
Advanced maternal age ( ≥ 40 ys) or any other risk factor for POF
At least Two of the following three features:
A previous POR (≤ 3 oocytes) with a conventional stimulation
protocol
An abnormal ovarian reserve test
(AFC 5-7 follicles or AMH ≤ 0.5-1.1ng/ml)

9. In 2011, a panel of experts in reproductive medicine
gathered together in an ESHRE Campus on poor responders
held in Bologna with the aim to find a common and
universal definition of poor ovarian response trying to find
simple, clearly defined, and reproducible criteria. The
Bologna ESHRE criteria represent the first real attempt by
the scientific community to unify the many definitions
proposed to identify poor responder patients by establishing
a definite point from which to begin and how to find
therapeutic strategies

10. It was concluded that “poor ovarian responders” should be
considered patients having at least two of the following criteria:
(BOLOGNA CRITERIA)
A previous episode of poor ovarian response (≤3 oocytes) with a
standard dose of medication1
An abnormal ovarian reserve with AFC <5–7 follicles or AMH <0.5–
1.1 ng/mL2
Women above 40 years of age or presenting other risk factors for poor
response such as previous ovarian surgery, genetic defects,
chemotherapy, radiotherapy, and autoimmune disorders
3
OR
Two previous cycles with < 4 oocytes are sufficient to define POR
Any other criteria in the absence of ovarian stimulation define the
expected poor response

11. Two cycles <4 oocytes
One cycle<4 oocytes-cycle + age >40
Onecycle <4 oocytes-cycle + abnormal marker ov reserve
Age >40 and/abnormal markers (Expected POR)

13. The occurrence of poor esponse to ovarian stimulation is not
infrequent; the prevalence of poor responders varies in the
literature between 9 and 24%*. This range is wide as it
depends on the definition of a poor responder that
individual IVF centers employ.
Data from the ASRM1 /SART- registry showed that 14.1% of
initial cycles were cancelled; at least 50% of these were poor
responders**
* Venetis CA et al, 2010.
** Fertil Steril. 2007.
- American Society for Reproductive Medicine
- Society for Assisted Reproductive Technology

15. The etiology of poor response to ovarian stimulation is
unknown. Despite being highly correlated with maternal
age, the condition is also common in younger women in
whom low ovarian reserve represents the most frequent
etiological factor
In addition, low ovarian reserve may be associated with
advanced endometriosis, prior ovarian surgery, pelvic
adhesions, increased body mass index, or smoking
However, this condition might also occur, unexpectedly, in
young women who are non-smoker and have apparently
normal ovarian reserves

16. Elder patients
High FSH, small ovaries
Ovarian surgery especially endometriosis
Genetic defects
Chemotherapy
Radiotherapy
Autoimmune disorders
Single ovary
Chronic smoking

17. Diabetes mellitus type 1
Transfusion – dependant B- thalathemia
Uterine artery embolization for the treatment of uterine liomyoma
Predicting ovarian response before starting hormonal stimulation
is the only way to adminster an efficient and safe treatment

18. FSH: Cut – off point ˃ 11 IU/L
Sensitivity = 10 – 30%
Specificity = 83 – 100%
AMH: Cut-off points ≤ 0.5-1.1 ng/ml
Sensitivity ˃ 75%
Specificity ˃ 85%
AFC: Cut-off points ≤ 5-7
Snsitivity 60 %
Specificity 85%
* Kwee et al. Fertil sterli 2008; ASRM practice committee, Fertil steril 2012.

19. When standard dose (225-300 iu) fails
Dose increase up to 450 IU
This approach is used since years
(classical approach)
But Now, Recent studies
No enhancement in ovarian response OR
Better pregnancy rates

22. Combination of gonadotropins & GnRH agonists started
on the luteal phase of previous cycle, considered the
protocol of choice in Normo responder patients
Lower cancelation rates & increased number of pre
ovulatory follicles and better pregnancy rates
But in poor responders it may induce excessive ovarian
suppression….

23. To dercrease the length supression (short and ultrashort, mini and
microdose flare up regiemens)
To lower or to stop ( after pituitary suppression)
To use the GnRH antagonist in combination with gonadotropins to
prevent premature LH rise

24. In a recent meta analysis
No statistically siginificant difference was present in clinical
pregnancy rates between GnRH agonist stopped protocol and the
standard agonist protocol
Moreover duration of stimulation and total number of
gonadotropins as well as number of oocytes retrieved were not
siginficantly different between the two groups

25. 50 studies included ( 34 studies reported on general IVF patients
10 studies reported on PCOS patients
6 studies reported on poor responders

26. In general IVF patients, ongoing pregnancy rate was significantly
lower in the antagonist group
Compared with the agonist group (RR 0.89, 95% CI 0.82–0.96).
In women with PCOS and in women with poor ovarian response,
there was no evidence of a difference in ongoing pregnancy between
the antagonist and agonist groups (RR 0.97, 95% CI 0.84–1.11 and RR
0.87, 95% CI 0.65–1.17, respectively)
Subgroup analyses for various antagonist treatment schedules
compared to the long protocol GnRH agonist showed a significantly
lower ongoing pregnancy rate when the oral hormonal
programming pill (OHP) pretreatment was combined with a flexible
protocol (RR 0.74, 95% CI 0.59–0.91) while without OHP, the RR was
0.84, 95% CI 0.71–1.0

27. Subgroup analysis for the fixed antagonist schedule demonstrated
no evidence of a significant difference with or without OHP (RR
0.94, 95% CI 0.79–1.12 and RR 0.94, 95% CI 0.83–1.05, respectively)
Antagonists resulted in significantly lower OHSS rates both in the
general IVF patients and in women with PCOS (RR 0.63, 95% CI
0.50–0.81 and RR 0.53, 95% CI 0.30–0.95, respectively)
No data on OHSS was available from trials in poor responders

34. Studies have shown that poor ovarian response is the first sign of
ovarian aging (early ovarian failure or early menopause)
This is clinically displayed by a shortened follicular phase which
limits the time available to recruit an adequate number of follicles

35. • Suggested mechanisms for poor ovarian response include:
Decreased number of FSH receptors in granulosa cells
Defective signal transduction after FSH receptor binding
An inappropriate local vascular network for the distribution of
gonadotropins
The presence of autoantibodies against granulosa cells
An excess of vascular growth factor receptor (VEGFR-1)
Abnormality in IGF-I and IGF-II levels
Diminished circulating gonadotropin surge-attenuating factor (GnSAF)
bioactivity

36. Ovarian response to follicle-stimulating hormone (FSH) action
differs considerably among women
Recently, new insights have been gained in the investigation of
variability in the gene that encodes FSH receptor (FSHr) gene or
genes of the estrogen pathway
Several polymorphisms of the FSHr gene have been discovered,
but Ser680Asn and Thr307Ala are the two most studied

37. The clinical implications of this finding are highly important;
the ultimate goal is to apply genetic markers as routine diagnostic
tests before ovarian stimulation to predict ovarian response,
determine the required FSH dose, and avoid the possible
complications related to FSH stimulation
The Ser680Asn polymorphism of the FSHR gene has been found
to influence the ovarian response to FSH stimulation in women
undergoing in vitro fertilization (IVF), and in women with the
genotype Ser/Ser, in whom the FSHR appears to be more
resistant to FSH action

38. Despite being difficult, it is of extreme importance to predict
who will be a poor responder, because stimulation protocols
should be individualized according to the conditions of each case
However, several tests have been proposed to predict ovarian
reserve, which can give an idea about the ovarian response besides
clinical variables (age, BMI)
• These tests include static and dynamic tests.
Static1
Dynamic2

39. BiochemicalA
• Based on single measurement of early follicular phase (cycle days 2–4).
High levels of serum FSH (>12 or >15 mIU/mL) on cycle days 2 or 3.
In regularly cycling females, only high levels of basal FSH is an accurate
prediction of poor response. This test is not suitable as a diagnostic test but
only as a screening one for counseling purposes in the first IVF attempt
0
1
Elevated FSH/luteinizing hormone (LH) on day 3 blood tests0
2
Elevated levels of serum estradiol (>30 or 75 pg/mL) on cycle days 2 or 3.
The clinical applicability for basal estradiol as a test before starting IVF is
limited by its very low predictive accuracy for poor response
0
3

40. BiochemicalA
• Based on single measurement of early follicular phase (cycle days 2–4).
Decreased levels of serum inhibin B (45 pg/ mL) on cycle days 2 or 3 are
considered to be more predictive. (In regularly cycling women, basal
inhibin B is accurate only at a very low threshold level
0
4
Reduced production and bioactivity of GnSAF0
5
Low insulin-like growth factor (IGF-I) in the follicular fluid0
6
Decreased serum concentrations of antimullerian hormone (AMH)0
7

41. AMH is a glycoprotein produced by the granulosa cells within
pre-antral and early antral follicles
Serum AMH levels closely reflect the size of the growing cohort
of small follicles which are sensitive to gonadotrophin
stimulation, making AMH an ideal predictor of ovarian
response during COH
Use of AMH has overcome the intercycle variability observed
with other markers. Intercycle variability is a problem as
women who may have displayed normal ovarian reserve on a
single measurement may, in fact, have poor ovarian reserve if
this was measured in a number of different cycles.
On the contrary, AMH can be measured at any time of the
menstrual cycle

42. In 2002 de Vet et al. published a landmark paper that reported
a 38% decline in AMH levels over a mean period of only 2.6
years in a group of young ovulatory women.
This large decline in AMH over a relatively short period of
time was not accompanied by any significant changes in antral
follicle count, serum FSH or inhibin B levels, suggesting that
AMH was the most sensitive maker of ovarian reserve

43. Sonographic testsB
• Have also been proposed as predictors of ovarian response. These include:
Decreased ovarian volume (OVVOL): It is hardly suitable as a routine test for
ovarian reserve assessment . A meta-analysis showed that ovarian volume
measurement with a cut-off value of 3 cm 3 had the specificity for the prediction of
cycle cancellation and non-pregnancy of 92% and 93%, respectively*
0
1
Decreased antral follicle count (AFC): The accuracy of the AFC for predicting
poor response in regularly cycling women is adequate at low threshold levels.
It will not be suitable as a diagnostic test, but it may be used as a screening one
directing further diagnostic steps in the first IVF attempt.
Another meta-analysis showed that women having AFCs less than four were more
likely to have cancelled cycles and less likely to get pregnant than women having
AFCs of four or more**
0
2
* Hum Fertil (Camb). 2009.
** Reprod Biomed Online. 2009.

44. Sonographic testsB
• Have also been proposed as predictors of ovarian response. These include:
Decreased ovarian stromal blood flow: The clinical value of doppler studies for
ovarian stromal blood flow has been unclear
0
3
* Hum Fertil (Camb). 2009.
** Reprod Biomed Online. 2009.

45. • Based on single measurement of early follicular phase (cycle days 2–4).
The clomiphene challenge test (CCT): It performs no better than other tests like the
AFC or basal FSH, especially because of a loss in specificity
0
1
The exogenous FSH ovarian reserve test (FSHORT)0
2
The GnRH agonist stimulation test (GAST). When used in regularly
cycling women, GAST showed a high degree of accuracy in the prediction
of poor response that could match that of AFC. However, it can be a
candidate for more extensive confirmation research
0
3
However, given the present level of evidence, dynamic ovarian
tests should not be used routinely

46. • Based on single measurement of early follicular phase (cycle days 2–4).
Recent evidence points that AMH and AFC may be better than
other tests, although other tests continue to be used and form
the basis for the exclusion of women from fertility treatments*
* Maheshwari A, et al “ Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy” Reprod
Biomed Online. 2009.

47. Overall, the effect of female age on the prognosis in poor
responders shows that older poor responders have lower
pregnancy rates (ranging between 1.5 and 12.7%) compared with
younger poor responders (ranging between 13.0 and 35%)

48. Only one study was found concerning pregnancy rates for poor
responders and the influence of BMI
Orvieto et al. (2009) described the pregnancy rate in subgroups
for BMI below or above 30 kg/m2
A significant decrease in pregnancy rate was found for the poor
responders with a BMI >30 kg/m2 versus a BMI ,<30 kg/m2 (4.5
versus 23%, respectively)
The age distribution of the patients in the two subgroups was
similar (32.4 SD+5.5 years versus 32.7 SD+4.5 years, respectively)

49. Age-adjusted AMH seems to have good sensitivity and
specificity for predicting ovarian response, with a false
positive rate of 10–20%
(Broekmans et al., 2006; La Marca et al., 2010; Broer et al., 2013)

50. High FSH dose
Alternative GnRH agonist protocol
GnRH antagonist
LH supplementation
Adjunctive treatments (DHEA, estradiol priming)

51. (Papathanasiou et al, 2016)
1 Antagonist
2 Microdose flare
3 Long protocol
4 LH added
5 Letrozole + FSH+antagonist
6 Adjunctive treatments (DHEA, estradiol priming)
7 Short protocol

52. (Papathanasiou et al, 2016)
8 Transdermal testosterone
9 Growth hormone
10 HCG added at stimulation
11 Increase of FSH dose
12 CC+ FSH/HMG + -antagonist
13 Luteal FSH start
14 Estrogen for luteal support

53. (Papathanasiou et al, 2016)
15 Follicular flushing
16 Long-stop protocol
17 FSH/HMG only (no agonist or antagonist)
18 FSH dose 300 IU
19 Late FSH start
20 Metformin
21 Ultrashorta-antagonist

54. (Papathanasiou et al, 2016)
22 Modified flare
23 Low-dose aspirin
24 Natural cycle
25 Mini-long protocol
26 Step-down of FSH dose
27 Luteal phase antagonist
28 Gamete intrauterine transfer

55. (Papathanasiou et al, 2016)
29 Day of embryo transfer
30 Early (Day 1) FSH start
31 FSH dose 450 IU
32 FSH dose 600 IU
33 Clomiphene citrate only

56. (Papathanasiou et al, 2016)

57. Although many protocols with different doses and types of
gonadotropins have been proposed in the literature over the
past 20 years for the management of poor responder
patients, to date there is no really efficient treatment that could
solve the problem of poor ovarian response and the current
question is still which is the ideal protocol for patients defined
as “poor responders”

58. Controlled ovarian stimulation” Gonadotropin “I
Type
Dose
Protocol (agonins vs antagonist)
AdjuvantsII
LabIII

59. Insufficient evidence to recommend one type of Gnt over another
Type
When the standard dose of gonadotropins(225–300 IU) fails to induce a
proper multifollicular growth, the obvious clinical approach is to increase
the dose
Dose
(Nardo et al, 2013)
(Haas et al., 2015)
review of literature: Patients who failed to conceive with 450 IU/d will not
benefit from increasing dose to 600 IU
It is today clear that these patients have a reduced ovarian reserve; the
recruitable follicles are fewer and the gonadotropins, independently of the
dosage administered, can only support the cohort of follicles receptive to
stimulation without manufacturing follicles de novo

60. `GnRH AnaloguesA
From the beginning of the nineties the combination of gonadotropins and
gonadotropin-releasing hormone (GnRH) agonists, started on the late luteal
phase of the previous cycle, has been considered the protocol of choice in
normoresponder patients
This approach lowers cancellation rate and raises the number of
preovulatory follicles and the number of oocytes retrieved and good quality
embryos for transfer, leading to better pregnancy rates
However this protocol could have a detrimental effect in poor responders
because it may induce an excessive ovarian suppression that could lead to a
reduced or absent follicular response

61. `GnRH AnaloguesA
• For this reason, in patients with poor ovarian reserve the options could be:
To decrease the length of suppression by decreasing the duration of GnRH agonist
use (short and ultrashort, mini- and microdose flareup regimens)
I
To lower or to stop (after pituitary suppression) the dose of GnRH agonists
initiated during the luteal phase
II
To use the GnRH antagonists in combination with gonadotropins to prevent
premature LH rise during the mid-late follicular phase
III

62. `GnRH AntagonistB
The most important advantages of the use of GnRH antagonist in
combination with gonadotropins are improvement of patient’s compliance,
decreased number of days of stimulation and of the amount of gonadotropin
administered, and statistically significant reduction of ovarian
hyperstimulation syndrome (OHSS)
Furthermore, GnRH antagonists are not administered during the stage of
follicular recruitment and thus suppression of endogenous gonadotropins
secretion is not present at that time in contrast to GnRH agonists being a
possible advantage during ovarian stimulation in this group of patients

63. `GnRH AntagonistB
However, based on the last Cochrane database, it seems that use of GnRH
antagonists, in the general population, may lead to a nonstatistically
significant reduction of the live birth rates (OR 0.86, 95% CI 0.69 to 1.08)
compared to GnRH agonist protocols, probably due to a different patient
population selected for this stimulation regimen
Thus , the use of GnRH antagonists in combination with gonadotropins is a
suitable protocol for poor responders
In fact, GnRH antagonists in the mid-late follicular phase during ovarian
stimulation prevent the premature LH surge while not causing suppression
in the early follicular phase, obtaining more natural follicular recruitment
without any inhibitory effect possibly induced by the GnRH agonist

64. `GnRH AntagonistB
As there is not a stimulation protocol that significantly improves the clinical outcome
in poor responder patients and that can be considered as a standard of medical care
practice, the use of GnRH antagonist regimens could have some advantages over the
GnRH agonist protocols
First, it is possible to assess the ovarian reserve by ultrasound on days 2-3 of
the cycle in which controlled ovarian stimulation is planned and decide
whether to initiate gonadotropins in the cycle where the probability of a
favourable response is optimal. In fact, patients with a mean follicle count of
<5 follicles have significant cycle-to-cycle variability in antral follicle count
from (−2 to +5 to −3 to +7 )
Second, with use of GnRH antagonist to prevent premature LH rise we can
utilize a new gonadotropin, a hybrid molecule with a prolonged half-life
(corifollitropin alfa) that supports the cohort of follicle receptive to
stimulation for seven days

65. (Tarlatzis et al, 2003)
(Song et al, 2014)
(Griesinger et al, 2006)
(Franco et al, 2006)
(Pu et al, 2011)
(Xiao et al, 2013)
(Nardo et al, 2013)
a Flare up GnRHa Vs long agonist protocol Better results
b Flare up GnRHa Vs Antagonist/Let protocol Better results
c GnRHa 'stop' Vs long protocol No difference
d Antagonist Vs long agonist Better No difference
e Antagonist Vs flare up protocols. Better

66. `Growth hormone1
4-12 IU of GH SC on the day of stimulation
Stimulates steroidogenesis, follicular development and responsiveness to FSH
Acts synergistically with FSH
May improve the number of oocytes
(Jia et al. 1986)
(Adashi & Rohan 1993)

67. `Growth hormone1
Expensive and routine use can not be justified
(Cochrane SR, Kotarba et al. 2002)

68. `DHEA supplementation2
Mild androgen
75 mg – 100mg/d for at least 12 w

69. `DHEA supplementation2
(Zhang et al, 2016)
Increase in AMH levels
Decrease in baseline FSH
Improves oocyte numbers
Embryo quality
Improve spontaneous PR
Improve IVF PR

70. `DHEA supplementation2
Available over the counter
Minimal side effects
Inexpensive

71. `Luteal phase E23
Pretreatment cycle is a natural cycle (no BCP)
About a week after ovulation GnRH antagonist is started {prevent
premature recruitment of follicles}, Estrogen {provides the young
follicles an optimal condition to grow in the future}
Stimulation medications are started on day 3 of the next menses

72. `OCP pretreatment4
Help ovarian response
GnRHan cycles: Adversely affects IVF outcome
GnRHa cycles: No effect
(Tarlatzis et al, 2003)
(Nardo et al, 2013)

73. `OCP pretreatment4
Help ovarian response
GnRHan cycles: Adversely affects IVF outcome
GnRHa cycles: No effect
(Tarlatzis et al, 2003)
(Nardo et al, 2013)

74. `Corticosteroids: contoversial5
Reduces the incidence of poor ovarian response
There is limited evidence
(Tarlatzis et al, 2003)
(British Fertility Society, 2014)
(Miell et al. 1993, Polak 1993, Smith et al. 2000, Keay et al. 2001)
1mg/d orally till retrieval
Directly influence granulosa cells via isoform or by increasing GH & IGF-1
Improve the endometrial microenvironment

75. `Nitric oxide donors6
The limited data are encouraging
(Tarlatzis et al, 2003)

76. `Growth hormone7
GH and IGF-1 levels in follicular fluid (FF)
Higher in successful IVF attempts
Decrease with aging
Lower in poor responders
GH adminstration increases IGF-1 levels
IGF-1 enhances LH- mediated androgen production within the thecal
compartment as well as FSH- mediated aromatiztion in GC
E2 levels in FF increased by GH therapy

77. `Growth hormone7
A systematic review and meta-analysis
The influence of different growth hormone addition protocols to poor
ovarian responders on clinical outcomes in controlled ovary
stimulation cycles
Medicine (Baltimore). 2017 Mar; 96(12): e6443. Xue-Li Li, MS,a Li Wang, MD, PhD,b Fang Lv, PhD,a Xia-Man
Huang, MS,aLi-Ping Wang, MS,c Yu Pan, MD,a and Xiao-Mei Zhang, MD, PhDa
Clinical pregnancy rate (RR 1.65, 95% CI 1.23–2.22), live birth rate
(RR1.73, 1.25–2.40), collected oocytes number (SMD 1.09, 95% CI 0.54–
1.64), MII oocytes number (SMD 1.48, 0.84–2.13), and E2 on human
chorionic gonadotropin (HCG) day (SMD 1.03, 0.18–1.89) were
significantly increased in the GH group

78. `Growth hormone7
The cancelled cycles rate (RR 0.65, 0.45–0.94) and the dose of
gonadotropin (Gn) (SMD –0.83, –1.47, –0.19) were significantly lower
in patients who received GH
Subgroup analysis indicated that the GH addition with Gn
significantly increased the clinical pregnancy rate (RR 1.76, 1.25–2.48)
and the live birth rate (RR 1.91, 1.29–2.83)

79. `Growth hormone8
Luteal estradiol priming could improve synchronization of the pool of
follicles available to controlled ovarian stimulation
In a meta analysis of 8 selected studies from 1227 initially searched,
the addition of estradiol in the luteal phase with or without the
semiltaneous use of GnRH antagonist decreases the risk of cycle
cancellation and increases the chance of clinical pregnancy in poor
responder patients

80. `Recombinant LH9
The meta-analysis indicated that rLH supplementation did not increase the
ongoing pregnancy rate in poor responders (OR 1.30, 95% CI: 0.80, 2.11)
Furthermore, there was no significant difference in the number of oocytes
retrieved, total dose of rFSH used, total duration of stimulation, number of
retrieved metaphase II oocytes and cycle cancellation rate between the study
and control groups
In conclusions, the available evidence does not support the addition of rLH in
poor responders treated with rFSH and GnRHa for IVF. It was inconclusive.

81. Action of LH at the follicular level in adose dependant manner increases
androgen production
Androgens are then aromatized to estrogens and help restore the follicular
melieu
Actuion of LH at GC level enhances responsiveness to FSH
LH has also a direct positive effect on final oocyte maturation

82. `Androgens10
Produced by Theca cells
Critical role in adequate follicular steroidogenesis and early follicular and
granulosa cell development
Increase FSH receptor expression in granulosa cells amplifying the effect of FSH

83. `Androgens10
Testosterone supplementation (three trials; n = 225) significantly improved CPR
(OR 2.4; 95% CI 1.16–5.04) and LBR (OR 2.18; 95% CI 1.01–4.68).
Aromatase inhibitors (four trials; n = 223) and dehydroepiandrosterone
supplementation (two trials; n = 57) had no effect on outcome
J Hum Reprod Sci. 2016 Apr-Jun; 9(2): 70–81

84. `Androgens10
61 trials including 4997 cycles employing 10 management strategies
Most common strategy was the use of gonadotropin-releasing hormone
antagonist (GnRHant), and was compared with GnRH agonist protocol (17
trials; n = 1696) for pituitary down-regulation which showed no significant
difference in the outcome
Luteinizing hormone supplementation (eight trials, n = 847) showed no
difference in the outcome
Growth hormone supplementation (seven trials; n = 251) showed significant
improvement in clinical pregnancy rate (CPR) and live birth rate (LBR) with an
odds ratio (OR) of 2.13 (95% CI 1.06–4.28) and 2.96 (95% CI 1.17–7.52)

85. `Androgens10
Increased number of small preantral/ antral follicles and granulosa/theca cell
proliferation by androgen treatment in primates
PCOS-like morphological/functional changes by exposure to extra ovarian
androgens.( e.g, congental adrenal hyperplasis, androgen producing tumors)
Basal T level realted to number large follicles on hCG day and pregnancy
outcome in poor responders
Up regulation of FSh receptor desity by androgens

86. `Aspirin11
Increased intra ovarian vascularity has been linked to improved delivery of
gonadotropic hormones or other growth factors required for folliculogenesis
On the other hand impaired ovarian blood flow could contribute to poor
ovarian response
Based on this rationale, by enhancing ovarian vascularization with vasoactive
substances such as aspirin, the ovarian response could theoritically improve

87. `Assisted hatching1
No benefit
(Tarlatzis et al, 2003)
(Kyrou et al, 2009)
(Mok-lin et al, 2013)
`
Embryo transfer on day 2
Vs day 3
2
Improve CPR
`Follicular flushing3
Does not increase the number of oocytes retrieved lower IR and CPR

89. According to available SR
The following interventions are associated with increase CPR in poor
responders
Flare up GnRHa protocol
Estrogen Primed Antagonist Protocol
DHEA supplementation
Transdermal testoeterone
Embryo transfer on day