management of poor responders in ivf by dr shashwat jani

Management Of Poor Response

Facts Or MythsDr. Shashwat Jani.

M.S. ( Gynec)Diploma In Advance Endoscopy.

Consultant Assistant Professor,Smt. N.H.L. Municipal Medical College,

Sheth V. S. General Hospital, Ahmedabad.

Mobile : +91 99099 44160.E-mail : [email protected]

May 1, 2023 Dr Shashwat Jani 9909944160 2


POOR RESPONDER ( ESHRE )

Two of the following three features must be

present:

Advanced maternal age (≥40 years) or any other risk factor

for POR;

A previous POR (≤3 oocytes with a conventional

stimulation protocol);

An abnormal ovarian reserve test (i.e. AFC <5–7 follicles or

AMH <0.5–1.1 ng/ml).


Bologna Criteria ( Ferraretti et al. ESHRE Consensus, Hum Reprod 2011 )

At least 2 of the following:1 ) Advanced maternal age (≥40 years or risk

factor for POR)2 ) Previous POR (≤3 oocytes with conventional

stimulation)3 ) Abnormal ovarian reserve biomarker AFC<5-7; AMH <0.5-1.1ng/MlOr:• Two episodes of POR after maximal stimulation


Management of Poor Responders

“ One of the most challenging tasks in

reproductive medicine...”


1. Identify Patient at Risk…


RISK FACTORS…o Elder patientso High FSH, Small Ovarieso Previous poor responseo Ovarian surgery especially in case of

endometrioma ,o Genetic defects,o Chemotherapy, o Radiotherapy,o Autoimmune disorders,o Single ovary,o Chronic smoking, o Unexplained infertility.


Moreover, New risk factors of low ovarian response have been proposed:

o Diabetes mellitus Type I .o Transfusion-dependent B - thalassemia ,o Uterine artery embolization for the treatment

of uterine leiomyoma .


“ Predicting ovarian response before starting hormonal stimulation is the only way to administer an efficient and safe treatment…”


Predictors of Poor Ovarian Reserve

Age, Biochemical parameters (basal FSH levels in the early follicular phase, Serum antimullerian hormone [AMH]), Morphological characteristics (antral follicular count [AFC] and ovarian volume)


• FSH: Cut - off point > 11 IU/L* Sensitivity = 10%-30% (nfalse-negatives) Specificity = 83%-100%

• AMH: Cut-off points <0.5-1.1 ng/mL Sensitivity >75% (efalse-negatives) Specificity >85%

• AFC: Cut-off points <5-7 Sensitivity >60% Specificity >85%

*Standardized assays by WHO IRP 78/549; Esposito et al. Hum Reprod 2002; Bancsi et al. Fertil Steril 2002;

Kwee et al. Fertil Steril 2008; ASRM Practice Committee, Fertil Steril 2012


2. Individualized Controlled Ovarian

Stimulation


1. GONADOTROPINS• When standard dose ( 225 – 300 IU ) fails …

Dose increased up to 450 IU.

• This approach is used since years….

( CLASSICAL APPROACH )


• But, Now, RECENT STUDIES ( Prospective & Retrospective ) :

No enhancement in Ovarian response OR

Better pregnancy rates.


Which gonadotropin preparationsoffer the highest oocyte yield?


Recent Studies, Increase of FSH starting dose does not result in higher pregnancy rates and also found no differences between the starting dose of 300UI, 450UI, and 600 UI of gonadotropins in terms of retrieved oocytes, number of embryos obtained, and pregnancy rates.


2. GnRH Analogues…Since the era of Nineties…. Combination of Gonadotropins & GnRH agonists ,

started on the late luteal phase of previous cycle , considered the protocol of choice in Normo responder pts.

Lower cancellation rates & Increased No. of

Pre ovulatory follicles & better pregnancy rates.


But, in Poor Responders...,It may induce

excessive ovarian suppression…

For this reason, in patients with poor ovarian reserve the options could be…


(i) To decrease the length of suppression by decreasing the duration of GnRH agonist use

(short and ultrashort, mini- and microdose flareup regimens).

(ii) To lower or to stop (after pituitary suppression) the dose of GnRH agonists initiated during the luteal phase .

(iii) To use the GnRH antagonists in combination with gonadotropins to prevent premature LH rise during the mid-late follicular phase .


In a recent meta analysis…• No statistically significant difference

was present in clinical pregnancy rates per cycle randomized between the “GnRH agonist stopped protocol” and the “ standard agonist protocol” .

• Moreover, duration of stimulation and total number of gonadotropins ampoules required as well as number of oocytes retrieved were not statistically different between the two groups.


3. GnRH Antagonists• Introduced 15 years ago …

Advantages : Increased Pt. Compliance. Decreased No. of days of stimulations Decreased amount of gonadotropins Reduction in OHSS.


• Recent meta-analysis of 14 randomized controlled studies,

“ GnRH antagonist protocols resulted in a statistically significant lower duration of stimulation compared with GnRH agonist protocols but there was no significant difference in the number of oocytes retrieved, in the cycle cancellation rate, and in the clinical pregnancy rate.


Advantages of Antagonists Over Agonists…

Possible to assess Ovarian Reserve by USG on D2 –D3 of cycle in which COS is planned.

With Antagonists , to prevent premature LH Surge , a new gonadotropins, a hybrid molecule with prolonged half life - Corifollitropin Alfa can be used.

It could exploit fully the reduced ovarian reserve by the rapid increase in the serum FSH concentration that would result in a significantly higher exposure of the small antral follicles to constant high levels of FSH during the early follicular phase.


To Strengthen the effect of Exogenous

Gonadotropins….

Proposed alternative Approaches…


1. ROLE OF GH GH and IGF-1 levels in follicular fluid (FF)• Higher in successful IVF attempts• Decrease with ageing• Lower in poor responders GH administration increases IGF-1 levels• IGF-1 enhances LH-mediated androgen production within the

thecal compartment as well as FSH-mediated aromatization in GC (beneficial effect on steroidogenesis)

E2 levels in FF increased by GH therapy (beneficial effect on oocyte quality)

Mendoza et al. Hum Reprod 2002; 2Bahceci et al. Eur J Obstet Gynecol Reprod Biol. 2007; 3Lucy MC. ReprodFertil Dev. 2011; 4Speroff & Fritz 2005; 5Tesarik et al. Hum Reprod 2005.


There are no very recent and robust data suggesting routine addition of GH in ovarian stimulation protocols for poor responders patients...!!!


2. Estradiol in Luteal Phase Luteal Estradiol priming could improve

synchronization of the pool of follicles available to controlled ovarian stimulation.

In a recent meta analysis of 8 selected studies from 1227 initially searched, the addition of estradiol in the luteal phase with or without the simultaneous use of GnRH antagonist decreases the risk of cycle cancellation and increases the chance of clinical pregnancy in poor responder patients.


3. Recombinant LH In a very recent meta-analysis of 40

randomized controlled studies , significantly more oocytes were retrieved and significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH VERSUS r-hFSH treatment in poor responders, suggesting that there is a relative increase in the clinical pregnancy rates of 30% in poor responders and that the addition of r-hLH to r-hFSH may be beneficial for women with poor ovarian response.


Rationale of LH supplementation

• Action of LH at the follicular level in a dose dependent manner increases androgen production

• Androgens are then aromatized to estrogens and help restore the follicular milieu.

• Action of LH at the GC level enhance responsiveness to FSH.

• LH has also a direct positive effect on final oocyte maturation.


4. ANDROGENS Produces 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 and thus potentially enhance responsiveness of ovaries to FSH.


DHEA A recent meta-analysis of four

randomized controlled trials of adjuvant androgens (DHEA and testosterone) in poor responder patients showed a significantly higher ongoing pregnancy rate in the androgen supplementation group.


TESTOSTERONE Increased No. 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., congenital adrenal hyperplasia, androgen-producing tumors, transsexuals)

Basal T level related to No. large follicles on hCG day and pregnancy outcome in poor responders.

Up-regulation of FSH receptor density by androgens (increased ovarian sensibility to FSH).

• 1Weil et al. J Clin Endocrinol Metab 1999; 2Hugues & Durnerin. Reprod Biomed Online 2005;• 3Frattarelli & Peterson. Fertil Steril 2004.


5. ASPIRIN 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 theoretically improve.


The conclusion of a meta-analysis and a systematic review was that clinical pregnancy rate per embryo transfer was not found to be different between patients who received low-dose aspirin and the control group.

On the basis of updated evidence, a low dose of aspirin has no substantial positive effect on the likelihood of pregnancy and it should not be routinely recommended for women undergoing IVF.


6. NATURAL CYCLES IVF Natural cycles IVF with or without minimal

stimulation can be considered as an easy and cheap approach in the management of poor responders.

In younger women ( < 35 years ) results are encouraging with pregnancy rate 18 % per started cycle, 29 % per transfer, 31% per patients.


7. Oocyte Cryopreservation Breakthrough in ART technologies. Major societies like ESHRE, ASRM , ASCO

acknowledged recently oocyte cryopreservation as a non experimental procedure which provides the required legal and moral support for widespread application.

Moreover, oocyte cryopreservation can also be used to preserve the fertility of all those women at risk to lose their ovarian potential over the time.


3. Management of poor responders in the IVF lab

Incomplete oocyte denudation Laser-assisted ICSI Standardization of lab environment

and culture conditions Oocyte/embryo banking with

vitrification Blastocyst culture for TE biopsy


4. TAILORING EMBRYO TRANSFER…

• D2 vs D3 vs D5• D6 ( or Frozen thawed blastocyst ) if TE biopsy.

Thank you …

management of poor responders in ivf by dr shashwat jani

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