Lecture for physicians explaining the significance of the duration of ovarian stimulation for the quality of the oocytes

1. Egg Quality and Term Stimulation
Dmitri Dozortsev, MD, PhD
2020

2. Based on

3. The new ovulation paradigm

4. Here is what insiders say about egg quality
«Give me a great egg and I will give you a great embryo»
Unknown embryologist
«Give me a great embryo and I will make a woman pregnant»
unknown REI

5. Defining Egg Quality
Egg quality (aka developmental competence) can be defined retrospectively as a
probability to become a child, once fertilized.
The only prospective marker of egg quality used clinically – presence
of the first polar body (“nuclear maturity”):

6. State of the art aim of ovarian stimulation
Harvesting as many eggs with the polar body
as possible, while mitigating the risk
of hyperstimulation
But, what if the presence of the 1st PB (“nuclear maturity”)-
is a weak benchmark of egg quality?

7. Ability to extrude 1st PB is a weak benchmark
Size and shape provide minimal information about maturity
Benchmarks of the developmental competency in the order of their acquisition during
maturation within the follicle: GVBD – PB1 extrusion – fertilization –
development to 2 cell stage – development to the blastocyst

8. Relative position of acquiring ability to extrude 1st PB
An ability to extrude the first polar body is a benchmark which could be
compared to the appearance of a sucking reflex in the otherwise immature fetus

9. But it works!
When in the thousand's years of the history of medicine,
a wrong assumption was a barrier to the successful practice?

10. Does a follicle provide information about egg quality?
Size and estradiol measurements are merely different way to quantify
the progress of the follicle (the box), but not the egg (the content of
the box).
That’s why the largest follicle may not contain the best egg

11. While follicle is small, the gradient of growth
factors (produced by the egg) prevents the
induction of FSH receptors in granulose.
Therefore, the egg controls the entire follicle.
At the recruitment into ovulatory cycle
Why follicle is not telling anything about the egg?
As an egg is losing control over the follicle to
FSH, its time for maturation is at the mercy of
the follicle (or an REI)
Therefore E2 and follicle size are do NOT tell
anything about the egg’s competency
GDF-9, BMP-15, SMAD
Before FSH receptors
FSH FSH

12. Measuring the follicle size
The same as measuring the size of the
abdomen to predict the day of term delivery
=

13. Time is the single most important parameter
«Darling, when did you have your last period»

14. Duration of biological processes is fixed by nature
It can’t be shortened with negative consequences:
Pregnancy
Puberty
Cell cycle
Stages of embryonic development
Maturation of champaign (9 months)
“Stop rushing me. I want to take my time falling in love with you.”
-- Ai Yazawa

15. Time is critical for egg’s competency
Epidemiological data
Short cycle is shortened due to follicular phase and linked to reduce fecundity
“Term maturation” 18 days – 37 hours.
fecundity
cycle duration

16. What determines the duration of the follicular phase

17. How critical may time be for egg’s competence?
Just as it is impossible to shorten pregnancy without consequences,
it may be risky for an egg to shorten the follicular phase
* percentage of fertilized eggs
developing to the blastocyst stage
after ovarian stimulation
Survival
99.9%
99.6%
99.5%
96.9%
85.5%
26.9% = %Bl*

18. Age-related changes may not be due solely to the eggs
High FSH
They may be related in part to ovarian cortex reduced
elasticity that results in shorter follicular phase
More granulose is recruited into mural
FSH
Follicles grow faster
Weaken ovarian cortex
+

19. Short stimulation
Many follicles
Risk hyperstimulation
Reduced percentage of competent eggs
Resolving paradox of low egg quality in young patients
(and PCOS)

20. The proposed goal of stimulation: term stimulation
1. Доза ФСГ
2. Диклофенак
3. Цетротид
Term maturation – 16.5 days
Follicular phase – 18 days

21. How to create term stimulation cycle?
estradiol – minimal stimulation – diclofenac – ignore the loss of the leading follicle
Tools to manage duration of stimulation:
Dozortsev, Pellicer and Diamond, Fert&Ster 2020
Dozortsev and Diamond, Fert&Ster 2020
cycle ~5 days
(male or female)
cycle ~30 days
Inflammation – the terminal phase of the follicular development

22. Case report (unpublished)
Cycle #2 12 days follicular phase
(diclofenac for the last 3 days)
Cycle #1 10 days follicular phase
6 weeks 1 day
6 weeks 3 days
Dozortsev, Tralik, Diamond and Allon, 2020
Patient: 34 years, clomid, timed intercourse

23. Realistic expectations of term stimulation
 We can improve over natural follicular phase only some time
 Time is critical, but it must be “quality” time: i.e. too much FSH may
recruit too many cells into mural granulose, leaving fewer granulose
cells to nurse the egg
 Low level of growth factors synthesis may not recruit and retain
adequate number of granulose cells
 The proportion of competent eggs varies greatly from female to female
 Only a certain percentage of women’s eggs are competent
 Other unknown intrinsic egg factors
1560 weeks 2 weeks of the follicular phase

24. «I get great result with short stimulation»
«with a very long stimulation embryos do not grow well»
If the stimulation becomes unintentionally protracted despite an
adequate amount of gonadotropins you are dealing with a pathology.
This requires an investigation.
How do you define “great results”?
«This cannot possibly be right, because»
30% of even deeply immature
babies survive, but this does not
make inducing birth at 25 weeks
feasible

25. «Data from the studies of chromosomal errors show
similar trend despite different duration of stimulation»
«This cannot possibly be right, because»
If an embryo was able to reach a blastocyst stage when
it could be chromosomally tested, it would be
expected to have a similar chance of chromosomal
errors irrespective of its prior history.

26. Conclusions
 Good stimulation must be “term”
 Measurable parameters of the follicle do not carry
information about an egg
 “Nuclear maturity” (1st PB) does not signal egg’s competence
 Stimulation can improve or decrease egg quality
 “Term maturation” is 16 days before the trigger
 “Term maturation” may need to be longer than 16 days for
older patients