Diminished ovarian reserve Flashcards
Bologna classification
2 of the following characteristics to be considered a poor responder:
-Maternal age 40+ or other RFs for poor response e.g. excision of bilateral endometriomas
-Poor response in previous cycles with retrieval of 3 or less oocytes in a conventional stimulation protocol (or a cancelled cycle for poor response)
-Low AFC <5-7 follicles or low AMH (<3.5-8pmol/L)
OR two previous episodes of poor ovarian response after maximal stimulation.
Poseidon criteria
Patient orientated strategies encompassing individualised oocyte number
Newer classification system
Moves from a concept of poor ovarian response to poor prognosis patients
Aims to stratify low prognosis patients on the combination of quantitative and qualitative parameters
Female age and egg quality, rates of aneuploidy etc make these groups more homogenous rather than the Bologna which is a heterogenous population of ‘poor responders”
Group 1 Poseidon
“Good reserve, good quality”
<35 years, AMH >8.6pmol/L or AFC >5
Type a) <4 eggs at previous OPU
Type b) 4-9 eggs at previous OPU
Possible reasons:
Insufficient gonadotrophin dose
Asynchronous development
Genetic polymorphism of FSH-R, LH-R
Trigger and/or oocyte pick up issues
Treatment suggestions:
GnRH antagonist max stim, consider priming (E2, testosterone - though no strong evidence)
consider LH supplementation
Number of oocytes needed to obtain one euploid blastocyst = 5
Group 2 Poseidon
“Good reserve, poor quality”
>/= 35 yrs, AMH >8.6pmol/L or AFC >5
Type a) <4 oocytes at previous OPU
Type b) 4-9 oocytes at OPU
Possible reasons:
Insufficient gonadotrophin dose
Asynchronous development
Genet polymorphism of FSH-R, LH-R
Trigger and/or oocyte pick up issues
Treatment suggestions:
GnRH antagonist max stim, consider priming (E2, testosterone, OCP - though no strong evidence)
consider LH supplementation
Number of oocytes needed to obtain one euploid blastocyst = 10-12
Group 3 Poseidon
“Poor reserve, good quality”
<35 years, AMH <8.6pmol/L or AFC </=5
Reasons for poor response:
Poor ovarian reserve
Asynchronous development
Management:
Max stimulation Consider long GnRHa protocol if doesn’t respond to antagonist, consider E2/androgen priming.
Need 5 oocytes to obtain one euploid embryo
Group 4 Poseidon
“Poor reserve, poor quality”
>/= 35 years, AMH <8.6pmol/L or AFC </= 5
Reasons:
Poor ovarian response
Asychronous development
High aneuploidy rate
Management: Max stimulation Consider long GnRHa protocol if doesn’t respond to antagonist, consider E2/androgen priming. LH supplementation.
Need 10-12 oocytes to obtain one euploid embryo
Definitions:
Ovarian reserve
Oocyte quality
Ovarian response
Ovarian reserve - the number of oocytes remaining in the ovary
Oocyre quality - potential of an oocyte to result in a live-born infant
Ovarian response - actual oocyte yield with ovarian stimulation
Ovarian reserve tests
Anit-mullerian hormone (AMH) - glycoprotein of the TGF-B (transforming growth factor B) family, produced by the primary, preantral and early antral follicles.
Antral follicle count (AFC) - total number of follicles across both ovaries between 2-10mm in size in early follicular phase
Early follicular FSH (with oestradiol)
Early follicular Inhibin B - glycoprotein secreted primarily by preantral follicles.
Clomiphene citrate challenge test (CCCT) - provocative test - now obsolete as AMH and AFC much more reliable.
Inhibin B as a marker of ovarian reserve
Ovarian reserve decreases –> inhibin B early follicular levels fall –> lower central negative feedback to pituitary –> inc FSH production –> results in high early follicular FSH –> earlier onset of new follicular growth –> inc in E2 concentrations –> decreases follicular phase length and therefore overall cycle
Basal serum FSH and E2
Elevated levels on day 2-3-4 in women with DOR.
Specific but not sensitive test for DOR (if normal reassuring, if elevated = non-specific)
Significant intra and intercycle variability - limits realiability.
E2 useful only as an aid to the correct interpretation of a normal basal serum FSH value.
If basal FSH if normal but E2 elevated in early follicular phase this can also indicate DOR.
Clomiphene citrate challenge test
measurement of serum FSH prior to (day 3) and after (D10), administration of 100mg of CC on cycle days 5-9.
Lower levels of Inhibin B and E2 –> neg feedback decreased on pituitary –> higher FSH. So after CCCT would see higher FSH levels and indicate DOR. It is not superior to non-dynamic tests for predicting POR or pregnancy after IVF and so has been abandoned.
AMH
Produced from granulosa cells of primary, preantral and early antral follicles.
Gonadotrophin independent and so stays constant throughout menstrual cycle.
Can be decreased by COCP (particularly those with lower levels of AMH).
More sensitive than basal serum FSH, tends to decline before FSH rises.
Ovarian volume
Reduces as women age.
Uncommonly used for clinical prediction given high inter and intracycle variability and general lack of sensitivity.
AFC
The sum of the number of antral follicles (2-10mm) in both ovaries, observed by TVUSS in the early follicular phase.
AFC has low intercycle variability and high interobserver reliability in experienced centres.
Which marker is the best?
AMH and AFC have been shown to be equivalent in multiple studies.
AMH testing is simpler and can be done at any time of the menstrual cycle.
AFC is a reasonable alternative.
No benefit in combined ORTs - no more useful than AMH or AFC alone.
Do ovarian reserve tests predict spontaneous conception/fertility (unproven and infertile populations)
NO
Unproven fertility population:
In prospective cohort studies, markers of ovarian reserve were poor predictors of reproductive potential as measured by fecundability (the probability of conceiving in a given menstrual cycle), cumulative probability of pregnancy, or incidence of infertility.
“Time to conceive” study prospective cohort of 750 woemn aged 30-44 years without known history or risk factors for infertility.
Findings: AMH <5pmol/L or FSH >10IU/L had similar CPR after 6 and 12 months compared to women with normal values.
Also shown that AMH did not predict probability of conceiving after unmedicated donor-sperm insem cycles.
Infertility populations:
ORT are no more useful than age alone in predicting unassisted pregnancy in women with infertility.
Don’t offer meaningful improvements over established pregnancy prediction models such as Hunault.
Do ovarian reserve tests predict treatment success
IUI-OS
Evidence suggests that ORT don’t predict likelihood of success from IUI-OS (further research required).
Mainly based on review of Diamond NEJM trial comparing multiple gestation with gonadotrophins, clomiphene and letrozole for IUI.
IVF -
Good at predicting oocyte yield
AMH as an independent variable is only weakly predictive of pregnancy at best
Ways to potentially improve outcomes with POR
Type of cycle
Dose of gonadotrophin
Aromatase inhibitors in cycle
Androgen priming
Oestrogen priming
Growth hormone
CoQ10
Autologous platelet rich plasma (PRP)
Cycle type with POR
ESHRE ovarian stimulation guideline:
1. GnRH antagonist and agonist cycles are equally recommended (conditional ++–)
Meta-analysis 2017 (Lamback) - no difference between long agonist and antagonist
2 RCTs showed no benefit in MDF over antagonist for CPR
Higher chance of cycle cancellation for DOR in antagonist cycles
- Clomiphene citrate alone or in combination with gonadotrophins, and gonadotropin stimulation alone are equally recommended for predicted poor responders. (Strong ⊕⊕)
Meta-analysis only compared CC with GnRHagonist cycles.
An RCT not included in the meta-analysis, also investigating the combination of CC and gonadotrophins in an antagonist protocol in 250 poor responders. A significantly lower clinical pregnancy rate (5.9% vs. 14.1%) was reported with CC addition. (Schimberni, et al., 2016).
Androgens
Androgen receptors (AR) are expressed in theca cells, granulsa cells and ova and are critical for folliculogenesis and ovulation
Rationale for using androgens is that they may help to facilitate transition of quiescent follicles to the growing pool, thus increasing pre-antral and antral follicles and also augment FSH receptors on granulosa cells thus improving ovarian response to FSH
But keep in mind excess levels as seen in PCOS can lead to follicular arrest
Various androgens, mainly testosterone and DHEA have been clinically tried as a co-treatment before and during stimulation
Cochrane review 2024 - moderate certainty evidnece that pretreatment with T improved LBR in those with DOR.
Meta-analysis on pretreatment with androgens in DOR - showed testosterone had a higher live-birth rate (risk ratio, 2.09; 95% confidence interval, 1.11-3.95
But recent multi-centre, multi-national double blind placebo controlled RCT (T-Transport) looking at pre-treatment with transdermal testosterone in POR did not show increase in clinical pregnancy rates compared to placebo - this hasn’t yet been published, only reported in abstract form at ESHRE, not included in recent cochrane.
DHEAS – no evidence of benefit in LBR identified in Cochrane review or - meta-analysis 2022
ESHRE - Use of testosterone or DHEAS before ovarian stimulation is probably not recommended for poor responders. (conditional ⊕⊕⊕)
Aromatase inhibitors
ESHRE
Addition to an FSH cycle probably not recommended in poor responders (conditional ++–) - Bechtejew, et al., 2017 meta-analysis showed no benefit.
Dose of FSH for poor responders
It is unclear whether a higher gonadotropin dose is recommended over 150 IU for predicted poor responders. (Conditional ⊕)
There is evidence that a higher gonadotropin dose than 150 IU results in a higher number of oocytes in poor responders, and more chances of having an embryo for transfer. However, there was no difference in live birth/ongoing pregnancy rates. Furthermore, the sample sizes of the studies are small and therefore not sufficient to provide evidence for dose comparisons for live birth outcome.
A gonadotropin dose higher than 300 IU is not recommended for predicted poor responders. (strong ⊕)
Cochrane 2024 showed no difference in LBR by tailoring dose of FSH (low certainty evidence). OHSS rate was reduced by tailoring (low certainty evidence)
Hormonal pretreatment prior to IVF theory behind potential benefit
Aim to suppress or to reduce LH and/or FSH secretion prior to gonadotrophin stimulation in IVF cycles. They are used by clinicians for different purposes such as synchronisation of follicular development, prevention of occurrence of early large follicle or spontaneous LH-surge, reduction of cyst formation.
Can also be used for clinic scheduling purposes.
Includes oestrogen, progesterone, testosterone and COCP.
Oestrogen priming
Theory - synchronise follicular recruitment
Pre-treatment with oestrogen before ovarian stimulation using the GnRH antagonist protocol is probably not recommended for improving efficacy and safety.
Cochrane review showed higher number of eggs with oestrogen pretreatment but not a difference in clinical pregnancy rate or live birth
Growth hormones
The biological rationale, GH 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.
2021 Cochrane Review by Sood et al - The use of adjuvant GH in IVF treatment protocols has uncertain effect on live birth rates and mean number of oocytes retrieved in normal responders. However, it slightly increases the number of oocytes retrieved and pregnancy rates in poor responders, while there is an uncertain effect on live birth rates in this group à interpret with caution – individual studies small, risk of bias and dose and regimen of GH used in trials was variable. Still need more data.
ESHRE - Use of adjuvant growth hormone before and/or during ovarian stimulation is probably not recommended for poor
responders. Conditional ⊕⊕
Co enzyme Q 10
Hypothetically, CoQ10 would reduce mitochondrial oxidative stress resulting in improved oocyte competence.
Essential component of mitchondrial electron transport chain. ATP production.
In a 2018 RCT by Xu et al of 186 POR pts (posideon group 3) – more oocytes were retrieved in CoQ10 group, higher fertilisation rate and inc. no of high-quality embryos compared to control. But clinical PR and LBR did not reach statistical significance (but there was a tendency to be higher in CoQ10 group)
Management options pretreatment
Adjuvants to stimulation
CC/Letrozole (improve endogenous FSH as well as exogenous) - no improvement in LBR.
Growth hormones
Androgens - DHEA, testosterone
Melatonon/CoQ10
Ovarian PRP
Aspirin
Pituitary suppression
Modifications of oocyte maturation and lab techn qiues
Dual trigger
Artificial oocyte activation
Blastocyst transfer
pretreatment pituitary suppresson
prevent late luteal phase FSH rise
GnRH antagonists, E2 priming and OCP haven’t been shown to improve LBR
melatonin
Potent anti-oxidant. Underpowered for CPR.
ovarian PRP
Ovarian rejuvenation
1. adult human ovaries retain ovarian stem cells.
2. OSC do not feed into fucntional foolicular pool
3. OSCs can be activated in adult life to produce functional follicles
In vitro activation
Was investigated in women with POI or DOR.
NOT recommended by ESHRE.
Involves mechanical fragmentation of ovarian tissues with addition of enzymes (PTEN and others) into a solution to stimulate activation of dormant follicles, before ovarian tissue autologous transplantation.
Can also use drug free IVA.
Recommendation
Considering the limited efficacy, potential high cost, and safety
concerns, IVA of dormant follicles is considered experimental
and can only be applied within strict research protocols.
