Recommended
To replace
Aim
Protocol
Natural cycle IVF
Unstimulated IVF
Spontaneous cycle IVF
Single oocyte
No medication
Modified natural cycle IVF
Seminatural IVF
Controlled Natural IVF
Single oocyte
hCG only
GnRH antagonist and FSH/HMG add back
Mild IVF
Soft stimulation IVF
Minimal stimulation IVF
Friendly IVF
2–7 oocytes
Low dose FSH/HMG, oral compounds and GnRH antagonist
Conventional IVF
Standard IVF
Routine IVF
Controlled ovarian stimulation IVF
≥8 oocytes
GnRH agonist or antagonist along with conventional FSH/HMG dose
Mild IVF stimulation is defined by ISMAAR as the administration of:
1.
Low doses or fewer days of exogenous gonadotrophins in GnRH antagonist co-treated cycles
2.
The use of oral compounds (like antiestrogens or aromatase inhibitors) with or without gonadotrophins with antagonist co-treatment for ovarian stimulation
The aim of mild stimulation is to limit the number of oocytes obtained to less than eight.
12.3 Mild Stimulation Protocol
The concept of “FSH Threshold” and “FSH Window” forms the basis of all our stimulation protocols. FSH threshold being the level of FSH required to initiate follicular growth and FSH window is the time frame for which this FSH level plateau’s to obtain cohort recruitment. Drop in FSH levels following rise in estradiol level is responsible for selection of the dominant follicle. It follows then that the wider the FSH window, the more the follicles recruited [4]. Thus, in conventional IVF, multifollicular recruitment is achieved by administering a high dose of gonadotrophins for a longer duration; thus keeping the FSH window open for a longer time. In mild IVF a moderate elevation is sought since the aim is to have a small cohort of follicles; hence, the gonadotrophin dose is reduced. In the conventional protocol, follicular recruitment is totally dependent on exogenous FSH since the pituitary is downregulated. In the mild stimulation protocol, on the other hand, initial recruitment is by the endogenous FSH rise in the late luteal phase. Exogenous FSH added subsequently (cycle days (CD) 2–5) prevents decrease of FSH levels inducing multifollicular development by preventing follicular dominance [5].
12.3.1 Drugs Used for Ovarian Stimulation (OS) in “Mild Stimulation Protocol”
Both oral and injectable ovarian-stimulating agents can be used since the pituitary is not downregulated. The drugs used are:
1.
Gonadotrophins – rFSH, uFSH, and uHMG
2.
Antiestrogens – clomiphene citrate and tamoxifen
3.
Aromataze inhibitor – letrozole
12.3.1.1 Gonadotrophins
Gonadotrophins with or without oral ovulogens still remain the mainstay of OS. The choice between recombinant and urinary drugs is a question of availability and economics since it has been shown unequivocally that there is no difference in outcome [6].
Dose of Gonadotrophin
The dose of gonadotrophin is kept at 75–150 IU starting from days 2–5 of the cycle. A fixed daily dose of 150 IU rFSH compared with 100 IU/day was found to be more effective in inducing multifollicular growth when ovarian stimulation was started on CD5 [7]. The starting dose of gonadotrophin in the conventional protocol varies between 225 and 300 IU though it may be lower in PCOS patients.
Day of Starting Stimulation
Gonadotrophin administration can be initiated from cycle days (CD) 2–5 in the mild protocol, while it starts from CD2 in the conventional protocol. A cancellation rate of almost 15–20 % is observed when starting from CD5 because of mono- or bifollicular response. Starting on CD2 allows for more follicles to be recruited. De Jong et al. suggested that ovarian stimulation could be initiated as late as CD7 [7]; however, the number of women showing multifollicular development with this protocol was lower than with those starting stimulation on CD2–5 [8], and it never became popular.
12.3.1.2 Clomiphene Citrate (CC)
CC is an antiestrogen and has been used very successfully in ovulation induction for many decades. Trounson et al. were the first to use CC for OS in IVF in 1981 [9]. Once gonadotrophins were introduced they replaced CC as they were far more effective in getting a multifollicular response. Introduction of GnRH agonist for pituitary downregulation in IVF protocols spelt a death knell for CC since CC needs an intact hypothalamo-pituitary-ovarian axis for its action. The reintroduction of this antiestrogen came about with the use of antagonist in IVF. Addition of CC reduces the dose of gonadotrophin required for stimulation [10], thereby reducing the cost of the IVF cycle. The dose used is 50–100 mg for 5 days from cycle day 2 along with 150 IU of gonadotrophin. The dose of CC has not been standardized. CC can be used by itself as well; however, the number of follicles recruited is lower, and its antiestrogenic effects can be detrimental to implantation.
12.3.1.3 Aromatase Inhibitors (AI)
AIs inhibit the aromatization of androgens to estrogens thereby providing a negative feedback to the pituitary. In addition, the increased intraovarian androgens increase the sensitivity of the antral follicles to FSH [11] and may increase the number of pre-antral and antral follicles [12]. Advantage over clomiphene is thus twofold – no antiestrogenic effect on the endometrium and no depletion of E2 receptors [13] and an improvement of antral follicle sensitivity to FSH thus improving recruitment. The dose varies from 2.5 to 5 mg daily for 5 days starting from cycle day 2 and is administered orally.
AIs have been used with gonadotrophins extensively in poor responders and patients requiring fertility preservation as it keeps the E2 levels low. At present letrozole is an off-label drug, and its use as an ovulation induction agent is banned in India due to concerns about teratogenicity.
12.3.2 Preventing the Premature LH Surge
GnRH analogs are used in IVF to prevent the premature LH surge. The agonist has been in use for more than 20 years, and after many years of experience, it has been established that the long downregulation regime gives the best results in IVF. The antagonist was introduced in 2000 and after some initial hiccups is slowly gaining ground.
12.3.2.1 GnRH Antagonist
GnRH antagonists prevent the premature LH rise by competitive binding to the pituitary GnRH receptor. This leads to an immediate suppression of gonadotrophin secretion. Unlike the GnRH agonists, they do not cause an initial flare of FSH and LH, and there is rapid recovery of pituitary action once the effect wears off in 24 h.
GnRH antagonist is typically started as a daily injection of 0.25 mg administered s/c, in a fixed protocol from CD5/6 or a flexible protocol when the follicle size is between 12 and 14 mm and E2 >200 pgm/ml/. This allows the use of endogenous FSH action for initial follicular growth and helps to reduce the dose of gonadotrophins. It is also given as a single dose of 3 mg s/c, but this is not available in India.
The advent of GnRH antagonists with its rapid and reversible action brought to fore a surge of protocols using oral and a combination of oral and injectable ovarian-stimulating agents. These protocols helped to reduce the physical and financial burden of ART treatment. The introduction of antagonist protocols was met with a lot of skepticism since they were reported to give lower pregnancy rates [14]. The ease of administration and reduced medication used in patient especially one’s with poor ovarian reserve overrode these concerns, and as experience grew with the drug, claims of lower pregnancy rates were nullified [15]. Antagonist protocols using gonadotrophin only and a combination of clomiphene citrate/letrozole with gonadotrophins are popular for mild stimulation IVF.
12.3.2.2 GnRH Agonist
Long downregulation protocol involves starting GnRH agonist in the luteal phase of the previous cycle. This protocol is the most favored IVF protocols. Deep suppression of the pituitary necessitates the use of heavy doses of gonadotrophins for ovarian stimulation. So mild stimulation protocols cannot be used effectively with agonist suppression. GnRH acts by receptor depletion, and hence there is an initial gonadotrophin flare from the pituitary. Protocols using this action of the agonist are called “agonist flare protocols.”
Two major problems associated with agonist suppression are the need for higher doses of gonadotrophin with a consequent increase in the chances of hyperstimulation and almost 21 days of agonist injection.
12.3.3 Implications of Mild Stimulation IVF
Acceptance of any IVF protocol is intimately connected to the pregnancy rate and live birth rate achieved. This, in turn, would depend on the oocyte and embryo quality and alterations in endometrial receptivity. Physical and emotional burdens of a regime also play an important role.
Van der Gaast et al. have shown that the ideal number of oocytes after a conventional long protocol is 13 [16]. When the number is lower or higher, the pregnancy rate is compromised. In this context, aiming for a lower number of oocytes would seem both contradictory and counterproductive. The reduction in complications reduced physical and emotional burden, and the reasonable pregnancy rates achieved with mild stimulation have obligated physicians to consider this approach to improve patient experience. Reduced oocyte numbers obtained through mild stimulation appear to differ from reduced numbers obtained in the conventional regime. It appears that poor oocyte yield after classical ovarian stimulation probably reflects a poor ovarian response to FSH and that is associated with poor IVF outcome. However, low number of oocytes after mild stimulation probably represents a “quality selection,” i.e. stimulation of only the most mature follicles which result in high-quality embryos and in a pregnancy.
12.3.4 Comparison of Pregnancy Rates
Studies have compared the success rate of mild vs. standard ovarian stimulation in women with normal and poor ovarian reserve. In fact the advantage of mild stimulation was first recognized in poor responders.
12.3.4.1 PR in Women with Normal Ovarian Reserve
Three RCTs compared mild with the classical stimulation regimen. Pooled data showed an ongoing pregnancy rate per started cycle of 15 % in the mild group and 29 % in the conventional group showing that mild stimulation is not as effective as the conventional strategy [17]. Freeze-thaw cycles were not included in these studies. Inclusion of freeze-thaw cycles would improve the CPR (cumulative pregnancy rate) in the conventional group, as cycles with mild stimulation may not generate supernumerary embryos.
Of the three RCTs, the first by Hohmann et al. [18] included 142 normal responders who were divided into three groups: group A, long downregulation protocol, and groups B and C, antagonist protocol. In group B stimulation was started on CD2, and in group C it was started on CD5. Gonadotrophin dose was 150 IU. There were no differences in PR between the three groups though women in group C had a higher cancellation rate because of insufficient response.
Baart et al. [19] compared mild protocol with the conventional long downregulation protocol in 111patients. A dose of 150 IU of rFSH was started from CD5 in the mild group and 225 IU in the long protocol. The ongoing pregnancy rate per started cycle was 21 % in the “mild” group and 18 % in the control group, which was not statistically significant. PGS was performed on these embryos, and there were fewer numbers of aneuploid embryos in the mild stimulation group.
The largest RCT by Heijnen et al. [20] included 404 women who had approximately 800 cycles. In this study, the group with mild stimulation had a selected single embryo transfer, while the conventional group had two embryos transferred. The number of oocytes retrieved was lower, and the pregnancy rate per cycle was significantly lower in the “mild” stimulation group (17.6 % vs. 28.6 %, p < 0.0001). The patients however tolerated this protocol better, and the rate of discontinuation of treatment was lower. The cumulative live birth rate after 1 year of IVF treatments was comparable in the two groups (43.4 % with mild protocol, 44.7 % with the conventional regimen); the twinning rate was also significantly lower in the “mild” stimulation-SSET transfer group (0.5 % vs. 13.1 %, p < 0.0001). According to the authors, a reduced chance of birth per cycle in the “mild” regimen might be compensated by the increased number of IVF attempts in a fixed time.
Ovarian aging, ovarian reserve, and high BMI predict the risk of insufficient response to “mild” stimulation, and a predictive model has been developed in order to minimize the need of cancelling [21].
12.3.4.2 Women with Poor Ovarian Reserve
OS of women with poor ovarian reserve is beset with problems and frustration. Despite high doses of gonadotrophins, oocyte yield remains poor, and cancellations are high. It has been the trend to use doses as high as 600 IU to achieve good follicular recruitment. Unfortunately such strategies have not proven very useful [22] primarily because you cannot force out of a bank what it does not have. The poor pregnancy rates cannot justify the greatly increased cost of medicine; hence, there has been a shift toward mild stimulation.
Land et al. [23] observed that the IVF outcome of patients given a starting dose of 225 FSH UI/day vs. those receiving 450 UI/day was similar, even though more oocytes were obtained with the higher dose. High gonadotrophin dosage may prevent cycle cancellation but provides no advantage in terms of pregnancy rate, live birth rate, or miscarriage rate. It is believed that high doses of FSH recruit “resistant” follicles rescuing them from atresia, but the oocytes that they host are of poor quality and usually do not result in the generation of good quality embryos [24].
CC/Gonadotrophin/Antagonist Regimes
Reduce the cost and physical burden of treatment. In most studies, gonadotrophins 150/225 IU are combined with CC in a dose of 50–100 mg/day for 5 days from cycle day 2, during the early follicular phase. Unfortunately there is a high rate of heterogeneity in studies.
Two randomized trials that compared CC/HMG antagonist protocol to conventional agonist protocol came up with contradictory results. In the study by Dhont et al. [25], there was a significantly higher cycle cancellation rates and lower pregnancy rates per cycle (p = 0.002). The study by Lin et al. [26] concluded that PRs were similar in the two protocols, gonadotrophin used and number of stimulation days, and a number of oocytes retrieved were lower in the CC group. A similar outcome was achieved by other authors in retrospective studies.
Aromatase Inhibitors
Aromatase inhibitors are administered orally and help to reduce the cost of treatment by reducing the requirement of gonadotrophins, especially in patients with poor ovarian reserve. Grabia et al. [27] observed a PR of 27 % in good prognosis patients. Most studies have used letrozole with the standard dose of gonadotrophins in antagonist protocols. Verpoest et al. [28] randomized 20 good prognosis patients for the use of 150 IU rFSH from CD2 with or without the addition of 2.5 mg letrozole. GnRH antagonist co-treatment was started from CD6. The use of aromatase inhibitors resulted in higher numbers of oocytes and a tendency toward higher clinical pregnancy rates per started cycle in the letrozole group.
In conclusion oral ovulogens in combination with gonadotrophins have a place in cost-effective mild ovarian stimulation treatments especially in poor responders. More RCTs however are needed to assess the true benefit of these protocols.
12.3.5 Comparison of Embryo Quality
High estradiol levels have a negative impact on the developmental and implantation potential of embryos [29]. An increase in aneuploid embryos has also been reported [30]. It has been hypothesized that ovarian stimulation might disrupt mechanisms involved in maintaining accurate chromosome segregation [31]. Baart et al. [19] found a higher number of aneuploid embryos in the conventional protocol suggesting that more oocytes do not necessarily mean more good quality or more chromosomally normal oocytes. These findings imply that mild stimulation selects less oocytes but with a better quality that lead to the production of euploid embryos.
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