New strategies of ovarian stimulation based on the

concept of ovarian follicular waves: From

conventional to random and double stimulation

Sesh K Sunkara

King’s College London

London, UKThe views expressed in this presentation are those of the presenter and do not necessarily reflect the views of Merck. This presentation is for medical education purposes only

©Monkey Business Images/Shutterstock; ©IM_photo/Shutterstock; ©Jomwaschara Komvorn/Shutterstock

Ultrasound-guided oocyte retrieval image reproduced from Edris F, et al. Gynecol Obstet (Sunnyvale). 2014;4:214.

Traditional IVF

Embryo transfer in a fresh IVF cycle

Ultrasound-guided oocyte retrieval

Traditional COS

• Pituitary suppression – GnRH analogue

• Ovarian stimulation – follicular

phase start

• Final oocyte maturation trigger –

hCG, GnRH agonist

Folliculogenesis

Guogeon Hum Reprod 1986

Follicle development is a continuous process

Baerwald Hum Reprod Update 2012

1 2

Follicle development is a continuous process

Baerwald et al., Hum Reprod Update 2012

1 2 3

Baerwald et al., Fertil Steril 2003

• Daily scans for 50 women (19 – 43 years) with regular menstrual cycles for 1 inter ovulatory cycle

• 68% had 2 waves, 32% had 3 waves• Ovulatory follicle emerged from the early follicular phase wave• Other waves were anovulatory

Follicular waves

Clinical application of multicyclic follicular waves

Luteal phase stimulation Late follicular phase stimulation

Dual stimulation

Gonadotrophin stimulation

Ovulation

None, GnRH antagonist or progesterone

hCG triggerGnRH agonist trigger

Day 15 or later

Gonadotrophin stimulation

Menstruation

Day 6 to 14

GnRH antagonist or progesterone

hCG triggerGnRH agonist trigger

Follicular phase stimulation → Oocyte retrieval → luteal phase stimulation → Freeze all

Freeze all

Freeze all with all non-conventional stimulation protocols

Clinical scenarios for non-conventional stimulation

• Urgent fertility preservation for oncology patients

• Social/ elective fertility preservation

• Oocyte donors

• Routine use

• Poor responders

• Fertility preservation

Luteal startLate follicular startRandom start

Double stimulation for oocyte/ embryo accumulation

Von Wolff et al., Fertil Steril 2009

• Prospective controlled multi-centre study of fertility preservation in cancer patients• Follicular phase group (28 women) vs Luteal phase start group (14 women)• Stimulation start days 1 -13 of menstrual cycle vs days 14 – 25• Short flare or flexible antagonist vs modified antagonist protocol – gonadotrophins

and antagonist started on same day

Kim et al., J Korean Med Sci 2015

• Retrospective comparative study• 22 women with cancer VS 44 normal infertile women• Random start - gonadotrophin started on any day (± letrozole) + GnRH

antagonist with lead follicle ≥14 mm VS• Conventional start (flexible GnRH antagonist protocol)

Luteal phase start for fertility preservation: clinical outcomes

Pereira et al., Gynecol Endocrinol 2016

• Limited clinical outcome data but initial data reassuring

• 56 FETs in the breast cancer group• CPR 39.7%/ FET, LBR 32.3%/ FET• Comparable to age matched non fertility preservation cohort – LBR 29%/ FET

Random start for elective oocyte cryopreservation

Pereira et al., Reprod Biomed Online 2017

• No significant differences between the groups

Qin et al., Fertil Steril 2016

Random start stimulation in an IVF programme

Random start stimulation in an IVF programme

Qin et al., Fertil Steril 2016

Dual stimulation

Sighinolfi et al., Reprod Biomed Online 2018

Random start dual stimulation

Sighinolfi et al., Reprod Biomed Online 2018

Kuang et al., Reprod Biomed Online 2014

Dual stimulation for poor responders: Shanghai protocol

Dual stimulation for poor responders

Ubaldi et al., Fertil Steril 2016

No significant difference in euploid blastocyst rate

Vaiarelli et al., Front Endocrinol 2018

Tsampras et al., Hum Fertil 2017

Duostim

Vaiarelli et al., Front Endocrinol 2018

Chen et al., Fertil Steril 2016

Reassuring perinatal outcomes

Progesterone primed ovarian stimulation (PPOS)

La Marca and Capuzzo Repro Biomed Online in press

• Progesterone modulates GnRH secretion by decreasing GnRH pulse frequency (Chabbert-Buffet et al., Steroids 2000)

• Progesterone prevents physiological oestradiol induced LH surge (Massin et al., Hum Reprod Update)

• High progesterone prevents LH surge by negative feedback on the pituitary

PPOS

• Option with

• Non-conventional stimulation protocols

• Double stimulation

• Fertility preservation

• ? Routine use

• Initial studies have shown PPOS to be effective (Kuang etal., 2014, Qin e tal.,

2016, Wang et al., 2016, Chen et al., 2017, Dong et al., 2017, Zhu et al., 2017)

Conclusions

• Follicular wave theory allows for follicular stimulation commenced

any time during the menstrual cycle

• Good ovarian response with good oocyte numbers and quality can be

obtained with random start of stimulation

• Allows for dual stimulation

• Random start and dual stimulation an advantage for emergency

fertility preservation

Conclusions

• Likely higher gonadotrophin consumption with late follicular and

luteal phase stimulation

• Progesterone effective in preventing premature LH surge during

ovarian stimulation

• Freeze all with random start and PPOS protcols

• Initial data on efficacy and safety reassuring but no RCTs so far

• Need for RCTs and longer-term safety data of children

Thank you