Any day start is a novel ovulation induction regimen. The advantage of this regimen is those for oncofertility planning.

1. Any Day Start
Dr Raju Nair
Director- Reproductive Medicine
Mitera Hospital, Kottayam, Kerala, India

2. Ovulation
Induction

3. Ovulation
Dominance
Selection
Recruitment

4. Conventional Stimulation…
• Exogenous gonadotrophins are used to
achieve supraphysiological levels during the
period of follicular recruitment to override
the process of dominant follicle selection and
enable multiple follicular recruitment
– (Macklon, 2006).
• Gonadotropin administration is initiated from
the early follicular phase onward to extend
the window of recruitment, allowing a larger
cohort of follicles to escape atresia.

6. Follicle
recruitment
3 important, distinctly different,
physiologic events:
Initial recruitment
Cyclic recruitment
• The initial transition of primordial
follicles from the resting pool into
the pre-antral growth phase
• The cyclic recruitment of a cohort of
antral follicles (2–5 mm) during the
menstrual cycle following puberty
• The preferential growth of the
dominant ovulatory follicle.

7. Antral follicle recruitment
Antral follicles 2–5 mm develop continuously,
while others have proposed that ‘cohorts’ or
‘waves’ of antral follicles develop in a cyclic
manner during the menstrual cycle.
Three separate theories of follicular recruitment
have been proposed.
– Continuous recruitment (Theory 1)
– Single recruitment episode (Theory 2)
– Follicular waves (Theory 3)

8. Continuous recruitment (Theory 1)

9. Cyclic recruitment:
Theory of a single recruitment episode(Theory 2)
• An ovulatory follicle is selected from a single follicular cohort that emerges following
luteal regression
• Antral fluid from follicles of the recruited cohort contains low concentrations of
estradiol but relatively high concentrations of androgens

10. The wave theory of follicle
recruitment( Theory 3 )

12. Most women (68%) exhibited two waves of follicle recruitment during the IOI,
while the remaining women (32%) exhibited three waves.
multiple follicular waves during the menstrual cycle provides a rationale for the
notion that ovarian stimulation therapy can be initiated at different times during
the cycle-Duo stim/ Random start

13. What causes follicular wave
• HPO axis and intraovarian regulators influence the follicular dynamics,
and the levels of FSH seem to be responsible for preventing atresia of
new follicular waves.
• Progestrone secreted by the corpus luteum seems to play a pivotal role in
the regulation of the development of major and minor follicular waves in
humans.
– High levels of serum progesterone during luteal phase induce pituitary
suppression through a negative feedback, and therefore in the minor waves the
final follicular maturation cannot occur.
• Evidence suggests a role for inflammatory markers in the regulation of
follicular wave dynamics . Specifically, variations of serum C reactive
protein
– Women with three follicular waves during IOI would have higher CRP
concentration than those with two waves

14. • An earlier studies showed that most of the luteal phase
follicles in women were atretic and not able to be
inseminated , leading to the concept that the follicular
development in the luteal phase represented an abnormal
reproductive event.
• Recent clinical evidences did not confirm this hypothesis:
some studies reported that the mature oocytes obtained
during the luteal phase can produce viable embryos and live
births, and thus suggested that also the anovulatory waves
can be utilized during COS

15. • The recognition of multiple waves of follicle development during the
menstrual cycle provides a new model for understanding human ovarian
follicular development.
• These observations suggest the possibility that ovarian follicles are
available for ovarian controlled stimulation throughout the menstrual
cycle independently of gonadotrophin fluctuation and that the resulting
oocytes are mature and competent for fertilization.
• ovarian stimulation can be completely disconnected from the menstrual
cycle with no impact on implantation rate if no fresh embryo transfer
takes place

16. New paradigm of human follicular dynamics
• The wave theory of follicle recruitment challenges the
classical concept of folliculogenesis and is the basis for
current RANDOM START OS protocols.
• The increasing knowledge of human ovarian follicular waves
opened new options for human ovarian stimulation and
oocyte retrieval that could improve the efficacy of IVF
– Follicular phase COS (FPCOS)
– Luteal phase COS (LP-COS)

17. Random start ..
• The follicular waves could be recruited by constantly high
concentrations of FSH.
• This new knowledge about ovarian function and, in particular,
the theory of a multicyclic development of follicles during the
menstrual cycle, resulted in the prospect of new approaches
to ovarian stimulation.
• Random-start ovarian stimulation protocols,
– administration of exogenous gonadotrophins randomly on any day of
the monthly menstrual cycle.

18. What is new
in
Reproductive
Medicine?

19. Why you need Random start?
• Main measure of success in IVF: Clinical Live Birth Rate (CLBR)
• Possibility to increase the number of the oocytes (to
optimize/maximize the number of oocyte retrieved according to
the age and the ovarian characteristics of each woman) retrieved
during a single menstrual cycle by fully exploiting the various
follicular waves could offer higher chances to find a
reproductively competent embryo, thus improving the live birth
rate per attempt.
• Efficient vitrification program for both oocytes and embryos in the
IVF clinics

20. Who needs this intervention ?
• Poor prognosis patients
– patients of AMA and/or with a poor ovarian reserve
• Patients at severe risk for iatrogenic infertility
– patients affected by a malignancy that requires a gonadotoxic treatment
• Oncofertility- Fertility preservation
– To speed up
• Egg donation program
– to accelerate the whole process

21. OVULATION
LUTEAL HALT
Conventional start
Follicular start Luteal start
Duo stim

23. Conventional start

24. Luteal Halt Protocols
• In order to decrease the potential delays for cancer treatment, breaking down of the
corpus luteum (to stop progesterone production) and initiating menses were proposed
once a patient was in the luteal phase.
• The use of GnRH antagonists has been explored as a method to induce corpus luteum
regression.
– The studies showed that after the administration of GnRH antagonist in the luteal phase (e.g., a
single 3mg dose or 2–3 consecutive daily 250 mg doses of GnRH antagonist), serum
progesterone levels decreased and menses ensued 2–4 days later: Anderson protocol
– Another protocol involves the use of oral contraceptive pills (OCPs) for 4–6 days and use of daily
250 mg dose of GnRH antagonist on the last 2–3 days of OCP treatment
• GnRH antagonists and gonadotropins were administered simultaneously during the luteal
phase of the menstrual cycle and have observed shorter treatment times due to not
awaiting for menses: Michael wolf protocol

25. Luteal Halt Protocol
OCP

26. Late follicular start
• Ovarian stimulation without GnRH antagonist was started if the
follicle cohort following the lead follicle was smaller than 12mm and
stayed smaller than 12mm before a spontaneous LH surge (Fig. 1c).
• After the LH surge, GnRH antagonist was started when the
secondary follicle cohort reached 12mm to prevent premature
secondary LH surge
• If the follicle cohort following the lead follicle reached 12mm before
the spontaneous LH surge, pituitary suppression with GnRH
antagonist was initiated and continued until triggering final oocyte
maturation.

27. late follicular phase
If follicle size is
< 12mm and
stayed < 12mm
before spon LH
surge If follicle size >
12 mm

28. Patient report when DF 18mm
Ovulation was induced with human chorionic gonadotropin
or GnRH agonist when the dominant follicle reached 18mm
in diameter and ovarian stimulation was started in 2–3 days
in luteal phase.

29. Luteal start
If the patient with cancer presented in the luteal phase or the ovulation was induced,
ovarian stimulation was started in the absence of GnRH antagonist
(Fig. 1e and f).
Similar to conventional COS, GnRH antagonist administration was initiated later in the cycle,
when the follicle cohort reached 12mm to prevent premature secondary LH surge

33. Double stimulations .Unsolved questions
• There is no scientific basis to choose the duration of interval between
first pick-up and the start of the second ovarian stimulation.
– All studies reported an interval of 1–5 days without significant difference in
terms of length of stimulation and number of oocytes retrieved.
• It is also not known what the ideal drug is for triggering:
– some authors have reported successful pick-up with the use of HCG even in the
first stimulation while the majority used GnRH agonist triggering.
• The utility of using a higher dose of gonadotrophin in the second
stimulation or an LH activity drug is still under investigation.

36. Safety ..
• Recent studies reported a similar number of euploid
blastocysts obtained after COS conducted with an
identical protocol in the follicular phase and luteal phase
of the same menstrual cycle in patients with reduced
ovarian response.
• Other authors reported the birth of healthy babies with
no birth defects after LP-COS.

37. Final comments
• The evidence of multiple follicular waves during a single menstrual cycle in women opened
important implications for the treatment of infertility. M
• Random start COS offers an efficient strategy for fertility preservation to save time for
anticancer therapies.
• To date few studies have been published reporting the efficacy of random-start protocols.
– preliminary results indicate that the number of total and metaphase II oocytes retrieved and fertilization rates are
similar in early follicular and random-start protocols.
• Random-start ovarian stimulation results in a similar length of ovarian stimulation and in
similar gonadotrophin use.

38. Final comments
• Duo- Stim can maximize the number of oocytes obtained per menstrual cycle, in turn increasing the
chance to obtain reproductively competent embryos in the shortest possible time, a crucial
perspective for patients with a short-term fertility because of AMA and/or with reduced ovarian
reserve.
• Long term effects of offspring born with these frozen embryos will definitely warranted.
• More randomized controlled trials are needed for a routine use.