Francisca Martinez1 , Pedro N. Barri1 , Buenaventura Coroleu1 and Marta Devesa1
(1)
Service of Reproductive Medicine, Department of Obstetrics, Gynecology and Reproduction, Hospital Universitario Quirón Dexeus, Gran Via Carlos III 71-77, Barcelona, 08024, Spain
Francisca Martinez (Corresponding author)
Email: pacmar@dexeus.com
Pedro N. Barri
Email: PERBAR@dexeus.com
1.1 Introduction
There has been a recent awakening of attention to luteal-phase stimulation (LPS) that could be explained by a combination of circumstances. First, there are physiological grounds to support the notion of this new approach [1–3], provided that it is possible to separate ovarian stimulation and endometrial maturation by stages in order to avoid desynchronisation between embryo and endometrium. Moreover, advances in cryopreservation of oocytes and embryos have made possible an almost total absence of gamete loss after cryopreservation [10, 20]. Also, it is increasingly common in in vitro fertilisation (IVF) to use the antagonist protocol in gonadotropin stimulation and agonist triggering, postponing embryo transfer to a later cycle, not only to avoid the risk of OHS but also with the aim of improving embryo implantation and pregnancy rates [9, 11]. Finally, recent data show that embryos obtained after luteal-phase stimulation may provide optimum pregnancy rates ([13, 14, 17]).
1.2 Physiological Bases
The classic form of conventional stimulation is based on the concept that it is necessary to obtain FSH levels above a certain threshold for recruitment of a follicular or wave cohort and the later decrease in FSH levels is the critical element for selection of the dominant follicle. The duration of the increase in FSH levels above a critical threshold determines the number of follicles that will be selected from the cohort for preferential growth: the so-called FSH window. A short duration of the FSH level above the threshold will make it possible to select a single dominant follicle, whereas if the duration of this FSH window is extended by exogenous gonadotropin administration, multiple follicles will be selected. In the natural cycle, the dominant follicle has the initial advantage of size over the subordinate follicles, containing more granulosa cells and more FSH receptors making it more sensitive to FSH. The subordinate follicles are incapable of growing in low FSH, and so they succumb to atresia [2]. Follicle selection has been described as the phenomenon for avoiding atresia, i.e. as a hierarchical progression of follicular atresia over the period between FSH increase and decrease.
Generally, it is observed every month that a dominant follicle is selected during the early-mid follicular phase (FP) of the menstrual cycle. However, the presence of developing follicles has been observed on more than one occasion during the menstrual cycle in some women (waves). Most women develop a major follicular wave in the follicular phase in which a dominant follicle is selected and one or two minor waves, in which dominance is not manifest, in a single interovulatory period [2].
According to these studies, there would be constant availability of viable follicles, also during the luteal phase, susceptible to respond to gonadotropin stimulation.
It was recently observed that pregnancy could be obtained after ovarian stimulation in two phases, in the absence of menstruation, confirming the existence of several waves of recruitable follicles for stimulation and maturation [5].
Ovarian stimulation can take place independently, separately from the phases of the endogenous gonadotropin cycle, without harmful consequences provided that there is no fresh embryo transfer, to avoid desynchronisation with endometrial developmental.
1.3 Applications of Luteal-Phase Stimulation
Luteal-phase stimulation (LPS) has been applied successfully in the following:
· Fertility preservation in patients with cancer
· IVF patients, normal population
· Egg-donation programmes
· Patients with low response
1.3.1 Luteal-Phase Stimulation for Fertility Preservation
Initial figures showed that viable embryos could be obtained from immature oocytes obtained in the luteal phase after in vitro maturation ([8, 16]).
Subsequently, several authors have published the outcomes of starting stimulation at any time in the cycle (random start) for fertility preservation in patients with cancer [4, 7, 19, 21, 22], which are comparable to those obtained following conventional stimulation. In some cases, a GnRH antagonist was administered prior to or simultaneous with the start of stimulation to obtain a fast luteolysis (Table 1.1). Cakmak et al. [7] compared the outcomes of conventional stimulation in patients with cancer: 93 were stimulated with recombinant FSH started in the follicular phase (FP) and 35, after random start (13 patients in late FP and 22 patients in luteal phase), adding letrozole to the rFSH in patients with hormone-dependent cancer. No differences were observed in the outcome.
Table 1.1
Studies reporting outcomes after random stimulation or LPS in patients with cancer for fertility preservation
|
Author |
Patients |
Treatment |
Oocytes recovered |
||
|
LPS |
FPS |
LPS |
FPS |
||
|
von Wolff et al. [22] |
12 |
28 |
rFSH-Antag |
8.5 |
11.5 |
|
Bedoschi et al. [4] |
2 |
rFSH-Antag |
12 |
||
|
Maman (2010) [16] |
5 |
13 |
IVM 150 FSH-10,000 IU hCG |
12.8 |
17.3 |
|
Nayak and Wakim [19] |
4 |
rFSH-Antag + GnRH bolus |
14–4 |
||
|
Sönmezer et al. [21] |
3 |
Letrozole 2,5 + rFSH |
9–17 |
||
|
Cakmak (2014) [7] |
22 |
93 35-R |
Letrozole-CC-HMG-GnRH bolus |
8.6 |
11 |
LPS luteal phase stimulation, FPS follicular phase stimulation, IVM in vitro maturation
1.3.2 Luteal-Phase Stimulation in an Egg-Donation Programme
Although the viability of luteal-phase stimulation had been demonstrated, there were no data on the evolutionary potential of the embryos obtained. For this reason, Martínez et al. [17] performed a prospective study on egg-donation oocytes, with the main objective of evaluating the clinical pregnancy rate in recipients of vitrified oocytes obtained after donor stimulation from the initial luteal phase of the cycle, comparing it with that of oocyte recipients obtained after stimulation in follicular phase. In this study, nine egg donors were recruited who did two consecutive stimulation cycles, one conventional stimulation cycle and another in luteal phase, 3 months apart (Fig. 1.1).
Fig. 1.1
Diagram of follicular phase stimulation protocol (day 2) and luteal phase (day 15)
After ultrasound evaluation and hormonal analysis, on day 2 of withdrawal bleeding after interruption of the contraceptive (D2), or on day 15 of post-withdrawal bleeding (D15), rFSH stimulation was started at a dose of 150–300 IU/day according to body mass index (BMI). Administration of the GnRH antagonist was added from the presence of a follicle >14 mm in the follicular phase, while in the luteal phase, it was started simultaneously with rFSH administration and was maintained until preovulatory triggering. Triggering took place with GnRH agonist when the presence of at least three 18-mm-diameter follicles was observed.
All the mature oocytes obtained after luteal-phase stimulation (D15) were vitrified. Following conventional stimulation (D2), some of the oocytes were vitrified and others were donated fresh. There were no differences in the dose of gonadotropins in the days of stimulation necessary or in the number of oocytes retrieved (Table 1.2).
Table 1.2
Dose of gonadotropins, days of stimulation, and number of oocytes retrieved among donors stimulated from day 2 or day 15
|
Donors |
D2 |
D15 |
|
Dose of rFSH (IU) |
2261 ± 940 |
2147 ± 535 |
|
Days of stimulation. |
10.44 ± 1.74 |
9.89 ± 1.2 |
|
No. of oocytes |
17 ± 6.65 |
22.5 ± 10.56 |
The unusual thing about this study is that it became possible to evaluate the two types of stimulation in the same population of women, since up to now, the two protocols had always been analysed in different groups of women.
The recipients received the standard treatment of endometrial preparation with estradiol valerate and vaginal progesterone. After warming the oocytes, they were inseminated with ICSI and one or two embryos were transferred on day 3 of embryo development. There were no statistically significant differences between the two groups in fertilisation, number of embryos transferred, and embryo quality. No differences were observed in the pregnancy rates per transfer (58.3 % in recipients of RD2 oocytes vs. 62.5 % in recipients of RD15 oocytes) (ns).
1.3.3 Luteal-Phase Stimulation in IVF Patients
Bearing in mind the outcomes obtained following random stimulation in patients for fertility preservation, an attempt was made to extrapolate the experience of LPS to IVF patients with the intention of developing a protocol that could be performed irrespective of the time of the cycle [6]. The authors performed a case–control study in which ten patients were treated with LPS (from days 19 to 21 of the cycle) and 30 patients with FPS (days 2–3 of the cycle) with rFSH and antagonist. They observed that a dose almost three times greater was required in the group treated with LPS. In both cases, the embryos were cryopreserved in 2PN with subsequent cryotransfer in artificial cycle, obtaining a pregnancy rate of 10 % in the LPS group compared with 61.3 % in the FPS group. The authors concluded that this concept was not applicable for routine use and its large-scale application should be studied further in fertility preservation patients.
Shortly afterwards, however, Kuang et al. (2014a) published the outcomes obtained in 242 IVF/ICSI patients after LPS, in which they froze all the embryos and later did the transfer in natural or artificial cycle. Stimulation was started immediately after confirmation of spontaneous ovulation and was done using an aromatase inhibitor (letrozole 2.5 mg/day) and hMG (225 IU/day). The authors point out that in this kind of protocol, there is no need for antagonist administration to inhibit the pituitary gland because there is no risk of endogenous increase in LH. They performed the final maturation administering a bolus of GnRHa (triptorelin 0.1 mg). No case of ovarian hyperstimulation was observed. Nor was there any premature increase in LH in the LPS cycles, compared to a 20 % increase observed among the cycles with conventional stimulation. A clinical pregnancy rate of 55.46 % (127/229) was obtained and a cumulative pregnancy rate of 64.7 % (112/173). At the time of publication, there were 48 births and 44 ongoing pregnancies, confirming the competence of the oocytes obtained after LPS and the viability of the embryos. This study is an important milestone because it was carried out in a large number of patients.
From the endocrine point of view, it is interesting that no premature increase in LH was observed among the LPS cycles, although there was no suppression of endogenous LH with the administration of a GnRH antagonist, compared with 27–25 % premature increase in LH among the follicular-phase stimulation (FPS) cycles, simplifying the need to monitor the treatment.
More recently, at the 2014 COGI Congress in Barcelona, Kuang (2014c) presented the current data from his group and announced that he and his group had given up on conventional stimulation and were routinely using LPS and transfer of cryopreserved embryos, with excellent outcomes.
1.3.4 Luteal-Phase Stimulation in the Low Responder
In 2013, Xu and Li [23] reported a case of “flexible ovarian stimulation” in a patient with low response in which, following intense ovarian stimulation and negative follicular aspiration, they continued the stimulation with FSH and clomiphene up to day 22. They retrieved one oocyte, which was fertilised and frozen and, after later cryotransfer, led to a pregnancy.
Later on, Kuang et al. [14] published their experience with the “Shanghai Protocol” of double stimulation during the follicular phase and the luteal phase in low response IVF/ICSI patients. The study was performed in 38 patients who met the Bologna criteria for low response. The first stimulation was performed with a combination of clomiphene citrate (25 mg/day) from the start until ovulatory triggering, letrozole 2.5 mg/day during the first 4 days, and hMG 150 IU every 2 days from that time until triggering with a GnRH agonist. They also added ibuprofen (600 mg/day) from the day of triggering to the day of aspiration to avoid early ovulation.
In the second stimulation started on the day of oocyte retrieval, after confirmation of the presence of at least two antral follicles, they used letrozole (2.5 mg/day) and hMG (225 IU/day) until the day of triggering. In no case did they use GnRH antagonist. The authors observed that the second stimulation provided a larger number of oocytes and embryos than the first did.
These results clearly show that a second stimulation can be started immediately following oocyte retrieval, achieving a considerable rise in the total number of oocytes and embryos obtained in the same patient.
Other authors [18] have included this “double stimulation” protocol for treatment of patients with low response, confirming the excellent results. In this group, the stimulation protocol used in the first and second stimulations was the same: FSH 300 IU/day and cetrorelix from D6 of stimulation and triggering with triptorelin 0.2 mg. The authors state that the “double protocol” was well tolerated by the patients and doubled the number of blastocysts finally obtained.
1.4 Discussion
We seem to be facing a real paradigm shift in ovarian stimulation in assisted reproduction techniques, which would improve the opportunities for patients in a variety of situations. The viability of stimulating the ovaries in the luteal phase has been demonstrated, with no apparent harmful effects for the time being, disconnecting stimulation from the fresh embryo transfer of embryos to avoid the phase lag with endometrial development, opening up a wide range of options.
Although the available evidence is still limited, it seems sufficient to think that LPS can offer a response that is at least quantitatively comparable to that of conventional stimulation ([6, 13, 14, 17]) (Table 1.3).
Table 1.3
Overview of studies published using luteal-phase stimulation (LPS) comparative and non-comparative with follicular-phase stimulation (FPS) in IVF patients, low response and egg donors, number of oocytes retrieved and pregnancy rates
|
Author |
Indication |
Patients |
Oocytes |
Pregnancy |
|||
|
FPS |
LPS |
FPS |
LPS |
FPS |
LPS |
||
|
Buendgen et al. [6] |
IVF |
10 |
30 |
8.8 |
9.97 |
10 % |
20 % |
|
Kuang (2014a) |
IVF |
242 |
13 |
53 % |
|||
|
Kuang et al. [14] |
Low response |
38 |
21 |
1.7 |
3.5 |
56.5 |
|
|
Martínez et al. [17] |
Donors |
9 |
9 |
16.7 |
22.5 |
||
|
Recipients |
8 |
12 |
62.5 % |
58.3 |
|||
The endocrinological changes documented by Kuang et al. [13] allow us to think of greater simplification in the monitoring of the treatment without fearing an increase in endogenous LH and even question the need to induce luteolysis to obtain a suitable response after ovulation, as has been proposed in fertility preservation [22].
With regard to the statement that LPS makes it possible to avoid the risk of OHS by not performing HCG triggering or embryo transfer (Kuang et al. 2014a), mention must be made of the OHS case described by Nayak and Wakim [19]. In a patient with cancer in whom triggering was with a bolus of GnRH agonist and after the use of antagonist during the randomly started stimulation for fertility preservation, the patient developed an OHS that required hospitalisation, paracentesis and thoracocentesis. As the number of cases is still very small, this aspect must be treated with caution.
Luteal-phase ovarian stimulation is interesting not only for medical or non-medical fertility preservation but also for patients with low follicular reserve in whom it would be especially worthwhile to make the best use of the various waves of folliculogenesis and retrieve the follicles that would go to atresia in a conventional IVF/ICSI protocol. The presence of small (<10 mm) antral follicles seems important for the successful start of LPS, as it has been suggested that the follicles with larger diameter, exposed previously to exogenous gonadotropins, could already have entered atresia and become incapable of providing a competent oocyte [13].
As for the pregnancy rates reported by the various authors, there does not seem enough to explain the discrepancy between the poor outcomes of Buendgen et al. [6] and those of other authors ([13, 14, 17]. It is true that the time of cryopreservation was different (embryos in 2-pronuclei stage, compared with oocytes or embryos on day 3). In protocols of this kind, it is essential to have an optimised cryopreservation programme for gametes and embryos.
In egg-donation programmes, it would make it possible not to lengthen the time between when the donor is ready to start stimulation and waiting for the next menstruation to start treatment. Even when a suboptimal number of oocytes are obtained after donor stimulation, stimulation without delay could be considered, which would optimise the final outcome of the procedure without excessively increasing the costs or inconvenience to the donor.
For all these reasons, we feel that the future is full of possibilities for luteal-phase ovarian stimulation, although more studies will be needed.
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