INTRODUCTION

Dual stimulation (DuoStim), as the name implies, means two controlled ovarian stimulation (COS) cycles for in vitro fertilisation (IVF) within one menstrual cycle with the purpose of maximising oocyte/embryo collection in a shorter period. It is used in cases undergoing COS for IVF where we anticipate that we may not be able to obtain an adequate number of oocytes by one stimulation cycle to achieve a live birth. Recent evidence on the physiology of follicular recruitment suggests that follicular recruitment by the ‘multiple wave’ theory within every menstrual cycle. It implies that two to three cohorts of antral follicles are recruited and available for stimulation in a single menstrual cycle, both in the follicular and luteal phases. This concept is contradictory to the previous understanding that follicular growth occurs only during the follicular phase of the menstrual cycle under the single wave theory of follicular recruitment.^[1]

DuoStim is a newer ovarian stimulation protocol used for COS in IVF first introduced by Kuang et al. in 2014 (Shanghai protocol), to collect embryos for poor prognosis women entering the IVF program.^[2] This method combines consecutive stimulations in the follicular and luteal phases of a single ovarian cycle to maximise the number of oocytes, hence embryos, formed within a cycle. It also needs to be understood that all embryos will have to be cryopreserved in the DuoStim protocol, ruling out the option of fresh transfer. This protocol could only be established after the development and standardisation of oocyte or embryo vitrification in contrast to the slow freezing programme used earlier. All embryos generated in these stimulation cycles are transferred in subsequent frozen thaw embryo transfer cycles only. This review aims to summarise the current evidence regarding the utility of DuoStim since it was first used by Kwang et al. in 2014 in poor responder women undergoing IVF cycles.^[2]

WHOM SHOULD BE CONSIDERED FOR DUOSTIM?

Poor responders are the ones for whom DuoStim was initially developed by Kuang et al. in 2014,^[2] and it is still the most common indication for this protocol. Almost 40% of women entering an IVF programme are poor responders belonging to any of the four Poseidon groups.^[3] They either have advanced maternal age, lower ovarian reserve or an unexpected poor response to stimulation. Another reason for undertaking the DuoStim protocol is when, despite an adequate number of oocytes obtained in the COS cycle, embryo conversion is poor, resulting in an insufficient number of embryos required to achieve a live birth. With increasing experience of using DuoStim in IVF, it has also become the preferred method of COS for women undergoing IVF for pre-implantation genetic testing (PGT) to collect more embryos in a limited period for the purpose of genetic testing for monogenic disorders or structural rearrangement. It can also be used for advanced maternal age women undergoing IVF for infertility to allow PGT for aneuploidy, since only 20% of embryos are euploid in women over 40 years of age.^[4] Fertility preservation is another common area for the use of DuoStim; it has been used for fertility preservation in cancer patients awaiting surgery or chemo/radiotherapy, where they have at least a month to undergo two stimulation cycles. However, in these patients, due to paucity of time, a random start protocol is more commonly undertaken, which can be started any time in a menstrual cycle to obtain oocytes/embryos for cryopreservation, not delaying the onset of their cancer treatment. Here the concept of multiple wave theory is applicable, like in the DuoStim protocol, enabling us to start stimulation during the mid-follicular, luteal, or mid-luteal phase also.

PROTOCOLS

Various regimes have been described in studies published on DuoStim since its first use in 2014 by Kwang’s group, with differences in stimulation protocols, methods of luteinising hormone (LH) suppression, type of trigger, and gap days between two stimulations.

Methods of LH Suppression

Different strategies have been adopted to prevent premature LH surge during FPS and LPS. These include the use of either a GnRH antagonist (GnRH-ant), progesterone, clomiphene citrate or ibuprofen [Tables 1 and 2]. Use of progesterone during LPS not only prevents premature LH surge but also avoids menstruation during oocyte retrieval (OCR), reducing the possible risk of infection. Progesterone-primed ovarian stimulation (PPOS) was introduced by Kuang et al. in 2015 for suppressing the LH surge in COS freeze-all cycles.^[10] It is now being extensively used in cases where fresh transfer is not planned, such as donor cycles, oocyte/embryo freezing for cancer patients, social reasons or cycles requiring PGT. However, the use of PPOS in DuoStim protocols to suppress LH surge in the luteal phase has been scarce as of now. Ours was one of the few studies to use medroxyprogesterone acetate (MPA) 10 mg per day in LPS to prevent LH surge [Figure 1].^[11,12] This also precludes the use of antagonists to control the LH surge, reducing the number of injections in LPS, thereby improving patient compliance and decreasing treatment cost.

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Figure 1:

DuoStim protocol used at our center.

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MERITS

DuoStim can increase the probability of attaining a live birth by significantly increasing the number of oocytes and usable embryos per menstrual cycle in comparison to conventional follicular stimulation alone, particularly in women with low ovarian reserve or poor responders. Regarding the performance of LPS vs. FPS in the majority of studies, LPS performed better than FPS in terms of the number of oocytes and usable embryos, including our study.^[5,12–14] A possible explanation could be the recruitment of a more synchronised antral follicle cohort in LPS due to high oestradiol levels during FPS and constant progesterone exposure post OCR.^[15] Gonadotropin stimulation and high follicular oestradiol levels may increase FSH receptor sensitivity in granulosa cells of pre-antral and small antral follicles, leading to a greater response in LPS.^[16]

One of the main benefits observed in most studies was reduced patient dropout rates, including our study. From a psychological perspective, the greater the couple’s expectations invested in their first attempt, the greater their disappointment in case of failure, and the higher the risk of treatment dropout. In our study, the majority of women with poor ovarian reserve or response and previous IVF failures agreed to undergo DuoStim after counselling, especially when a financial benefit was added to such cycles.^[12] Hence, in poor responders, dropout rates tend to be higher after failure of a single conventional IVF cycle, particularly when no oocytes or embryos are obtained. Our study found that LPS rescued 70% of cycles where no embryos were formed in FPS.^[12]

All studies have shown comparable oocyte and embryo competence obtained after FPS and LPS. Use of PPOS in the luteal phase makes DuoStim more patient friendly and cost effective by alleviating the need for antagonist injections and reducing frequent monitoring in LPS. In addition, it also averts menstruation during LPS, reducing the possible risk of infection during OCR.^[12,13]

DEMERITS

Studies have shown an increase in the number of days of stimulation required in LPS compared to FPS by 1–3 days. Researchers have tried to reduce it by increasing the time gap between the OCR day in FPS to as much as 5 days before starting luteal stimulation.^[8,12–14] The addition of letrozole at the beginning of luteal stimulation has also been proposed to help reduce days of stimulation by a few studies.^[2,7] There are also higher cycle cancellation rates in LPS compared to FPS, due to no response (22% in our study).^{[11,12,14,17]} Another demerit of LPS is the occurrence of menstrual bleeding during stimulation and/or during the subsequent OCR. This, apart from posing a risk of infection, may be a cause of apprehension to patients. However, it can be overcome by using PPOS in LPS instead of the antagonist protocol.^[12,13] The DuoStim protocol does not allow the option of fresh transfer; hence, mandatory freeze-all is necessary. However, in our study, the use of the hCG trigger in FPS allowed patients to opt out of the DuoStim protocol and undergo a fresh transfer in case of good embryo conversion.^[12] Currently, there is a lack of well-designed studies or a large, robust randomised controlled trial (RCT) analysing the effectiveness of DuoStim. We also need studies on the cost-effectiveness analysis of this protocol.

COMPARISON WITH OTHER NEWER STIMULATION PROTOCOLS FOR POOR RESPONDERS

CONCLUSION

Of all women undergoing IVF, protocols for normal and high responders have been very well delineated with the aim of reducing complications and optimising results. However, in poor prognosis women, the pursuit for an ideal protocol to optimise results and achieve successful live birth continues. This group mainly consists of women with advanced age or low ovarian reserve who, on one hand, have less time and on the other hand suffer extreme disappointment after one failed embryo transfer due to no surplus embryos. As a result, the burden of going through another stimulation cycle leads to a huge dropout rate in these women. Two stimulations within one menstrual cycle are proving to be a good tool to accumulate embryos in the shortest possible time, also reducing dropout rates significantly. Till we find a method to improve oocyte and embryo competence in ageing women undergoing IVF, such as mitochondrial transfer or a similar procedure, multicycle counselling using DuoStim or a similar protocol appears to be a relevant change needed in IVF. In women undergoing PGT for genetic disorder/aneuploidy or fertility preservation for cancers, this protocol appears suitable for embryo pooling. In most studies on DuoStim, LPS found a higher number of usable embryos compared to FPS. This advantage was not observed in reverse stimulations such as luteal followed by follicular (DuoStim fresh) or two subsequent follicular stimulations (BISTIM protocol). However, we need more robust RCTs to substantiate the effectiveness of the DuoStim protocol as an ideal protocol for this group of women undergoing IVF. The practical utility of offering such treatments must be to make such protocols affordable to support the couple’s chance of achieving a live birth to fulfil their dream of parenthood.