This document discusses ovarian reserve, its assessment, and strategies for managing poor ovarian reserve. It defines ovarian reserve as the quality and quantity of remaining oocytes. Key points are: 1. Ovarian reserve declines with age and can be predicted by antral follicle count (AFC), AMH, FSH, and patient history. 2. For poor responders, strategies include tailored stimulation protocols, LH supplementation, natural/modified cycles, and embryo cryopreservation to avoid OHSS. 3. OHSS risk depends on stimulation protocol and can be prevented by using a GnRH agonist or antagonist for final maturation instead of hCG.

2. Ovarian reserve
For assessing the success of IVF cycle we have to evaluate the
woman by
Age
Ovarian reserve
After this that we can : counsel the woman
tailor stim protocol

4. Ovarian reserve
It is the quality and quantity of the remaining oocyte at a given age
As it decline in these parameters with increasing age
Predictors of OR:
Age
CD2 FSH , INHIBIN B, E2
AFC
AMH

8. Nice guideline2013 depend on: AFC, AMH,
FSH
High
Poor R
16 or more
4 or less
Total AFC
3.5 ng/ ml or more
0.8 ng/ml or less
AMH
25 pmol/l
5.4 pmol/l
4 or less
8.9 or more
FSH iu/l

9. ESHRE October 2019 depend on:
1. AFC
2. AMH
with age the chance of producing a live birth in IVF program
decrease steadily to less than 10% per cycle more than 40 yr age
But still female age alone is not sufficient to judge fertility

11. FSH, Inhibin B, E2 and LH:
Inhibin B and E2 both produced by antral
follicle and suppress the release of FSH
So once follicle count decrease these horm
decreased (inhibin less than 45 pg/ml) and
so increase FSH indicate poor responder
but not much accurate.
E2 ≤ 20 or ≥ 80 pg/ml also indicate poor
responder. But studies showed E2 does not
add to the predictive values of other test
of OR.
These horm are correlated significantly
only in significant compromised OR

12. Basal FSH
It has diurnal variation , inter and intracyclical changes not expensive
No cut off point to predict poor OR s t up to 25 iu/l
Alone not used to document poor OR
So not used alone as a predictor
AFC by TV US
Small sacs with fluid filled , contain immature eggs,
2-9mm
Assessed at CD2
Its no. related to the pool from which they are recruited
Follicles more than 2mm are recruitable

13. Technical issues
Age (AF of 2-6 declining with age while 7-9 mm are usu
fixed)
Ethnic gr
Smoking
COCP users
Cancer pt

15. AFC and IVF outcome
Less 4 ---------- poor reserve
4 - 7 ------------ low count high dose of GN needed
8-12 ------------- intermediate
13-25 ------------ normal count, lower treatment doses needed, better
PR, lower cancellation rate, some OHSS
More than 25---- high responder, more OHSS, v good PR

16. AFC and the GNn Dosing
3 do not stim
4-7 225 iu rFSH +75 iu rLH from D2
225 IU r FSH + 150 IU from D2 if ≥37 yr
8-16 225 / 150 iu rFSH ( add LH 75 iu if low previous response)
More than 16 112.5/ 150 iu rFSH
More than 25 100 iu rFSH

19. AMH
Dimeric glycoprot exclusively produced by granulosa ceel of preantral (
prim and second fol)
It stay same level through out the cycle measure at any day
Function:
1. It inhibit the growth of primordial follicles and control the formation
of primary oocyte
2. Inhibit follicular recruitment by FSH
3. Decrease FSH responsiveness of preantral follicles , suppress the
aromatase activity , decrease LH receptors thus helps selecting one
follicle

22. factors decrease AMH
Age
Oophrectomy
Chemo/ radiotherapy
Gn administration
GnRh A
PREGN
CCOP
Type I DM
ethinicity
Factors increase AMH
PCOS
Adolesent type I dm
Not affected by obesity non
PCOS or RA

23. AMH and fertility
1. predicting ovarian response in IVF , it has sensitivity 80%, and
specificity of 70% in predicting poor response in IVF
It can predict excessive response OHSS of sensitivity and specificity of
82% and 76% respectively
2. Rational the program of ovulation induction.
3. Measuring ovarian aging and ovarian reserve.
4. Reproductive lifespan prediction, those delaying childbearing or
with poor reserve and want to freez.
5. AMH strongly correlate with basal AFC

24. AMH in PCOS
Granulosa cells produce more AMH in anovulatory PCOS than
ovulatory one
It is lower in obese PCOS than in normal PCOS one
AMH decrease with metformin treatment for 4-8 month
Available evidence does not support AMH to predict pregnancy but
studies found higher follicular fluid AMH correlate with better fertility
potential oocyte
Age both AMH and AFC had equivalent prediction of poor and excess
responder

33. Management strategies
Gonadotropin dosage
Natural and modified natural cycle
Alteration in stimulation protocol
LH supplementation

34. Androgen supplementation
Pretreatment with OCP
Luteal phase manipulation
Addition of Growth hormone
Day of embryo transfer

35. High-dose gonadotropins
Patients who responded poorly to conventional doses 150-225IU of FSH may produce more
follicles when given 300-350IU or even 600 IU per day. It is expected that an enhanced response
would lead to increase in the number of oocytes, embryos, and pregnancy rate. But recently this
approach not lead to enhancement of ovarian response or better pregnancy rate

36. GnRH agonists and poor responder
GnRH analogue and FSH
Use of gonadotropins and GnRH agonist in long luteal protocol
in normal responder lead to
Reduce cycle cancellation
Increase no of retrieved follicles
Better PR

37. But in poor responder this may lead to over ovarian suppression for this reason the poor
responder could have options
Decrease the duration of downregulation by
Stop the dose of GnRH agonist after suppression
Short, ultrashort, mini and microdose
or by Use of GnRH antagonist protocol

38. GnRH-agonist 'stop' or mini dose protocols
In this protocol GnRH administered in the long protocol, but agonist administration withheld
once gonadotropin stimulation started (after down regulation) in poor responders, no
spontaneous premature LH surges were recorded. This associated with higher number of
oocytes, but did not influence the reproductive outcome. In mini dose we reduce the dose to
half

39. SHORT PROTOCOL
Micro-dose GnRH-agonist flare protocol
In patients who fail to obtain adequate multifollicular growth with long protocol, use short and
ultra short protocol.The short protocol consists of early follicular phase initiation of GnRH-a, it
takes advantage of the initial agonistic stimulatory effect of agonist on endogenous FSH and LH
secretion.

40. Micro doses of GnRH-a (" reduced the dose to a quarter of that used in short protocol, for
example 50µg of leuprolide is given instead of conventional 200µg daily dose") used during the
1st days of the follicular phase (day2 or 3), and gonadotropins that were introduced several days
thereafter, may be after 3 days and continues with both treatment till day of hCG.

41. Antagonist protocol
One of the problems seen in poor responding patients is a shortened follicular phase, which
limits the ability to recruit a sizable cohort of follicles, so use antagonist before ovarian
stimulation in an attempt to lengthen the follicular phase, aiming to lengthen the recruitment
phase of the cycle to allow for the rescue of more follicles once gonadotropin stimulation was
initiated.

42. Advantages
Increased compliance
Decrease days of stimulation
Decrease no of injections
Low incidence of OHSS

43. Natural and modified cycle
the natural and modified natural cycle has a role in poor responders
especially in those who are refractory to COH and decline the option of
oocyte donation. But, there are some issues that have not yet been
subjected to testing such as:-
• Is modified natural protocol superior to natural protocol?
• What is the best timing of HCG injection and what is the ideal
time interval between HCG and egg retrieval?
• Are oocyte and embryo quality improved in natural cycle?
• How many attempts should be made?
• Should cleavage or blastocyst-stage transfers be performed?
• What is the dose of gonadotropins in modified natural protocol?
• Should LH be included in the gonadotropin regimen?
More research is needed before these questions can be effectively
answered

44. Addition of LH activity
With age and the onset of menopause endogenous LH as well as FSH
levels increase and testosterone levels decrease, the number of
functional LH receptors also decreases with age. Also endogenous LH
may be less biologically active or potent than it should be. It has been
suggested that follicular recruitment in women > 38 years old can be
improved by supplementing FSH stimulation with LH.
LH may improve oocyte cytoplasmic maturation by
*increased mitochondrial function and/or up-regulating DNA repair
enzymes.
*Either through E2 or some other intra-ovarian factor

45. Addition of HMG also
improved intra-ovarian autocrine-paracrine modulators,
it increases cumulus cell maturation
improved oocyte-cumulus cell interaction
improved cytoplasmic maturation of oocyte especially in patients with
high FSH/LH ratio.

46. Several studies showed that addition of LH result in
•Increase androgen which then aromatized to estrogen and help restore the follicle milieu
•Has role in oocyte maturation
•Enhance response to FSH
• More oocytes retrieved
•Higher PR

47. Androgen supplementation
• During early follicle growth before the follicle becomes sensitive to gonadotropins (By
reducing apoptosis?).
• Enhancing FSH action during the early gonadotropin-sensitive phase of follicular growth, by
increasing sensitivity to FSH and increasing FSH receptors.

48. 3 different strategies for androgen
Pretreatment with r LH
DHEA
Aromatase inhibitors

49. GH
GH itself increases follicular insulin-like growth factor 1 (IGF-1), improving the response to
gonadotropins, increasing oocyte competence and possibly increasing the DNA repair capacity in
oocytes. GH 8-12 IU from day 6 of stimulation till day of hCG, or 4-12 IU of GH sc, starting on the
day of ovarian stimulation with gonadotropins
But considering the extra cost and limited data available, there is not a well-established clinical
role for adjuvant hGH in the treatment of low responders at the current time.

50. Oral contraceptive pill pretreatment
OCPs have a putative role in enhancement of estrogen receptor sensitization due to their
estrogen content, also it reduces cyst formation

51. other strategies
Luteal phase manipulation
Low dose of aspirin
Assisted hatching

53. Ovarian Hyperstimulation Syndrome
(OHSS)
Is an iatrogenic complication of exogenous gonadotropin therapy that used to mature multiple
follicles for assisted reproductive treatments.
Ovarian hyperstimulation syndrome consists of ovarian enlargement accompanied by an
overproduction of ovarian hormones and a host of other ovarian vasoactive substances, which
alone or in concert may produce the hyperpermeability state responsible for the signs,
symptoms, and complications of OHSS.

54. Risk factors

55. Etiology and Pathophysiology
While the exact etiological factor responsible for the pathogenesis of OHSS is unknown, the
syndrome is known to be dependent on human chorionic gonadotropin (hCG). OHSS does not
occur if hCG is withheld, and ongoing hCG stimulation by early pregnancy is a significant risk
factor for persistent and severe OHSS. The fundamental physiological change in severe OHSS is
an increase in vascular permeability, resulting in a fluid shift from the intravascular spaces to
third-space compartments such as the peritoneal and thoracic cavities, often resulting in
hemoconcentration. The most important mediator in this process is thought to be VEGF(
Vascular endothelial growth factor).

56. Serum VEGF levels correlate with OHSS severity and hCG has been shown to increase VEGF
expression in human granulosa cells, which in turn raises serum VEGF concentration.
Numerous other mediators have been implicated in the disease process such as angiotensin II,
insulin-like growth factor and interleukin-6.

57. Classification of OHSS

58. Prevention of severe OHSS

59. The role of the stimulatory agent and
protocol
Earliest reports suggested a relationship between the type of gonadotropin preparation utilized
and the risk of OHSS but recently studies did not show significant differences among variable
drug regimens.
Indeed, numerous studies have shown that the method of stimulation (chronic low dose, step
up, or step down) carries far more weight as a risk factor than the type of injectable
gonadotropin used.

60. The use of GnRH-a in conjunction with COH, either as a ‘long’ or ‘short’ protocol, profoundly
affects the risk of OHSS. Both the long and the short GnRH-a protocols uniformly abolish the
midcycle luteinizing hormone (LH) surge. This suppression of the LH surge allows continued
stimulation by gonadotropins, which in turn will drive more follicles to full maturation, with a
consequent rise in serum E2 values and a markedly increased risk of OHSS.

61. The role of hCG and its substitutes
hCG as a surrogate for the midcycle LH surge is still universally used in COH for both ovulation
induction and IVF.
This ovarian action of hCG exerts a stimulatory effect on the putative ovarian substances which
directly promote, or may even be the causal factors in, ovarian hyperstimulation. Indeed,
angiotensin II, VEGF, TNF-α, and interleukins 1β, 2, or 6 are all either directly or indirectly
enhanced by hCG.

62. Recombinant LH and OHSS
The critical role of hCG in OHSS has encouraged many researchers to look for an alternate
substance to trigger ovulation.
Although exogenous native LH would constitute a physiological replacement, it has several
theoretical disadvantages, including its very short half-life of about 20 minutes. Because of this
short half-life, either huge doses or repeated administration would be needed to create a
sustained surge of at least 24 hours.

63. Recently, recombinant LH (rLH) has become commercially available to use as a midcycle
substitute to natural LH surge is now practicable in all kinds of COH, whether using
gonadotropins alone, clomiphene citrate in conjunction with gonadotropins, down-regulation
with GnRH-a, or with gonadotropinreleasing hormone antagonist (GnRH-ant).

64. GnRH agonists and OHSS
Alternatively, final follicular maturation and ovulation may be triggered using a GnRH agonist
This GnRH a gonist induced LH surge has a shorter half-life than exogenous hCG, resulting in a
less sustained luteotrophic stimulation and hence a lower risk for OHSS.
Clinicians must also be aware that because of pituitary desensitization, GnRH-a cannot be used
as an ovulation trigger for cycles in which GnRH-a was previously used for down-regulation.
If a patient at high risk for OHSS is identified and GnRH-a triggering is going to be use, a GnRH-
ant protocol, rather than a long-GnRH-a protocol, should be used for suppression of the
endogenous midcycle LH surge.

65. GnRH antagonists and OHSS
GnRH antagonists seem to be associated with a decreased risk of OHSS compared with the
GnRH-a long protocol in patients undergoing IVF, especially with the use of GnRH-ant, but
particularly for cetrorelix and less so for ganirelix.
Because of the competitive nature of GnRH-ant suppression and lack of desensitization, it is
possible to trigger ovulation with GnRH-a during co-treatment with gonadotropins and GnRH-
ant, a GnRH agonist trigger will displace the GnRH antagonist from the GnRH receptor to induce
a controlled surge of endogenous LH and FSH. This GnRH a gonist induced LH surge has a
shorter half-life than exogenous hCG, resulting in a less sustained luteotrophic stimulation and
hence a lower risk for OHSS.

66. Embryology strategies
Embryo cryopreservation for patients showing early signs of hyperstimulation can be an
important safety net in guarding against severe OHSS. With routine culture of embryos to the
blastocyst stage, it is possible to accurately assess the degree of OHSS prior to embryo transfer;
because blastocyst transfer takes place on the seventh day after hCG, absence of even a
moderate degree of OHSS is reassuring, and one may safely proceed with embryo transfer.

67. The higher implantation rates associated with blastocyst transfer have led some clinicians to
employ single blastocyst transfer in patients at risk of developing severe OHSS. Such a strategy
results in a negligible multiple gestation rate, which supposedly is associated with more severe
OHSS, presumably secondary to higher hCG levels.
Improvements in in vitro maturation of immature oocytes might also enable women, particularly
those with polycystic ovary syndrome (PCOS) who are at greatest risk of OHSS, to undergo
assisted reproduction using minimal if any gonadotropin stimulation. This may dramatically
reduce or eliminate the risk of OHSS.

68. Modalities for prevention of OHSS
adding metformin to gonadotropin regimens for ovulation induction.
Ovarian diathermy prior to initiation of COH.
Suppression of ovarian steroidal secretion.
Cabergoline use.
The anti-inflammatory action of corticosteroids has also been hypothesized to be beneficial in
preventing OHSS.
Low-dose aspirin therapy .
Coasting involves with holding gonadotropins while maintaining pituitary suppression with a
gonadotropin releasing hormone agonist or antagonist.

69. Triggering ovulation by low dose of human chorionic gonadotrophin.
Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase
support

70. Treatment of OHSS