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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
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©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
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Traditional COS
• Pituitary suppression – GnRH analogue
• Ovarian stimulation – follicular
phase start
• Final oocyte maturation trigger –
hCG, GnRH agonist
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Folliculogenesis
Guogeon Hum Reprod 1986
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Follicle development is a continuous process
Baerwald Hum Reprod Update 2012
1 2
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Follicle development is a continuous process
Baerwald et al., Hum Reprod Update 2012
1 2 3
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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
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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
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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
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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
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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)
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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
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Random start for elective oocyte cryopreservation
Pereira et al., Reprod Biomed Online 2017
• No significant differences between the groups
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Qin et al., Fertil Steril 2016
Random start stimulation in an IVF programme
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Random start stimulation in an IVF programme
Qin et al., Fertil Steril 2016
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Dual stimulation
Sighinolfi et al., Reprod Biomed Online 2018
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Random start dual stimulation
Sighinolfi et al., Reprod Biomed Online 2018
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Kuang et al., Reprod Biomed Online 2014
Dual stimulation for poor responders: Shanghai protocol
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Dual stimulation for poor responders
Ubaldi et al., Fertil Steril 2016
No significant difference in euploid blastocyst rate
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Vaiarelli et al., Front Endocrinol 2018
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Tsampras et al., Hum Fertil 2017
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Duostim
Vaiarelli et al., Front Endocrinol 2018
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Chen et al., Fertil Steril 2016
Reassuring perinatal outcomes
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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
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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)
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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
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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
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Thank you