Optimal Stimulation of Hypo-responders Undergoing IVF: a Prospective, Randomized, Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 150
- 试验地点
- 4
- 主要终点
- live clinical pregnancy
研究概览
简要总结
Stimulation is a key step of in vitro fertilization (IVF). Typically, injectable gonadotropins are used for stimulation, and their dose is individually determined to avoid hypo- as well as hyper-response. Despite the individualization some patients respond with a lower-than-expected number of oocytes. If the low response is unexpected based on the baseline parameters or if an unusually high dose of gonadotropins is needed to achieve a proper response we talk about "hypo-response". In such cases if the first treatment fails and a repeat attempt is planned typically even more gonadotropins, the combination of luteinizing hormone (LH) with follicle stimulating hormone (FSH) or the use of the more potent recombinant preparations are considered. The benefits of these approaches however have not been studied properly in hypo-responders. The studies have used various criteria to identify hypo-responders, have used various gonadotropin doses and have evaluated different outcome parameters. Live birth was only studied in one trial.
It is also known that in a different cycle the same patient is likely to have a slightly different response to the same type and dose of drugs. Therefore, the question arises whether a hypo-responder in one treatment is expected to have hypo-response again if the treatment is similarly carried out in a different cycle. Do we need to change/ increase the gonadotropin dose if based on age and ovarian reserve otherwise we would expect a normal response? Furthermore, if we consider a change should we increase the dose of FSH or should we combine it with LH?
Therefore the aim of this randomized controlled trial is compare an unchanged medication regimen to increased dose of FSH vs the combination of FSH and LH in hypo-responder patients identified based on POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria (Gr 1 and 2: retrieval of 9 or fewer oocytes in patients with an anti-Müllerian hormone (AMH) level ≥ 1.2 ng/ml or antral follicle count (AFC) ≥ 5 and age <35 years [Group (Gr) 1] or ≥35 years [Gr2]). Hypo-responder patients will be randomized to:
- Same gonadotropin dose as in previous treatment (recombinant(r) FSH) ['control group']
- The same dose as in the previous cycle but in the form of FSH + LH combination (rFSH:rLH 2:1 ratio) ['additional LH group']
- A dose increase of 75 international unit (IU) compared to the dose in the previous treatment. ['higher dose FSH group'] The primary outcome parameter to study is live clinical pregnancy. In addition, baseline demographic, stimulation and further clinical outcomes (pregnancy rate, miscarriage rate, live birth rate) will be compared.
详细描述
The key step of an IVF treatment is controlled ovarian stimulation. The aim of stimulation is to recruit an optimal number of oocytes. The outcome of the fresh cycle improves if the collected oocyte number increases up to 10-15 oocytes. Cumulative success however keeps on rising even over 20 oocytes.
In most of the IVF cycles injectable gonadotropins are used to induce multi-follicular development. The type and dose of the gonadotropins are individually determined based on age, ovarian reserve markers, weight and previous response to treatment. Based on these parameters patients are grouped as expected low-, normal- or high-responders.
Despite a seemingly adequate stimulation regimen some patients respond with fewer than the expected number of follicles/ oocytes. Such patients are called hypo-responders. According to the POSEIDON classification these patients belong to POSEIDON groups 1 and 2 (Gr 1 and 2: retrieval of 9 or fewer oocytes in patients with an anti-Müllerian hormone (AMH) level ≥ 1.2 ng/ml or antral follicle count (AFC) ≥ 5 and age <35 years [Gr1] or ≥35 years [Gr2]). Other definitions to identify hypo-responders are: 1) use of >2500 IU gonadotropins during stimulation, 2) lack of follicle growth during stimulation, 3) lack of estradiol rise during stimulation. In these cases, we expect a proper response, but it either does not happen, or we need to administer high doses of gonadotropins to achieve the desired result. The exact cause of this phenomenon is not known but receptor polymorphism is one mechanism that could interfere with appropriate signal transduction. Another hypothesis is that these patients are less sensitive to LH and despite adequate serum LH levels they suffer from a reduced LH effect.
If a hypo-responder patient needs to undergo a second treatment, usually either the gonadotropin dose is increased from the onset of the stimulation, or the FSH preparation is combined with LH, or the more potent recombinant preparations are favored. LH could play a dual role; it increases androgen synthesis in the theca cells which in turn increases the FSH sensitivity and aromatase activity of the granulosa cells. In addition, mid-size follicles express LH receptors and therefore LH can directly support their development.
According to one meta-analysis, if treatment outcome is compared with rFSH vs rFSH+rLH in the general, non-selected population then with rFSH more oocytes can be collected while the rFSH+rLH combination results in more pregnancies. Another meta-analysis focusing on poor responders found more oocytes and higher clinical pregnancy rates after rFSH+rLH treatment but no difference in the live birth rates.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •indication for IVF-ICSI
- •age 18-40 years
- •<9 oocytes in a previous IVF cycle and having an AMH ≥1.2 ng/ml and/or AFC ≥5 (POSEIDON 1,2)
- •The use of ≤225 IU FSH (either rFSH alone or the combination of rFSH+hMG) in the previous cycle
- •regular 24-35 day cycles
- •Intact uterine cavity
- •motile sperm from ejaculate or testicular biopsy
排除标准
- •not meeting the inclusion criteria
- •the use of rFSH:rLH (2:1 ratio) in the previous cycle
- •the use of clomiphene citrate or aromatase inhibitor in the previous cycle
- •>225 IU gonadotropin in the previous cycle
- •>3 failed previous treatments
- •patient with recurrent miscarriages
- •presence of a hydrosalpinx
- •positive HIV or hepatitis screening test
- •planned preimplantation genetic testing of the embryos
- •planned elective cryopreservation
- •lack of consent
研究组 & 干预措施
Control group
In this arm the hypo-responder patient will undergo stimulation using the same gonadotropin dose as in her previous treatment.
Treatment steps:
- Stimulation using the same recombinant FSH dose as in her prevoius cycle is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day.
- GnRH antagonist is started at follicle size 12-14 m.
- Trigger is administered once the largest follicle gets >17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval.
- Transfer of 1-2 embryos on day 3 or 5.
- Pregnancy test 12 days after ET.
干预措施: unchanged dose (Drug)
Additional LH group (Pergoveris, Merck)
In this arm the hypo-responder patient will undergo stimulation using the same gonadotropin dose as in her previous treatment but in the form of rec FSH and recLH 2:1 ratio (e.g.: if 150 IU rec FSH was used then 150 IU recFSH and recLH (2:1 ratio).
Treatment steps:
- Stimulation using the same dose as in her previuos cycle but in the form of recombinant FSH and recombinant LH 2:1 ratio is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day.
- GnRH antagonist is started at follicle size 12-14 m.
- Trigger is administered once the largest follicle gets >17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval.
- Transfer of 1-2 embryos on day 3 or 5.
- Pregnancy test 12 days after ET.
干预措施: use of combination of recombinant FSH and recombinant LH (Drug)
higher dose FSH group (follitropin alpha (Gonal-F, Ovaleap) or follitropin delta (Rekovelle)
In this arm the hypo-responder patient will undergo stimulation using recombinant FSH but with a dose increase of 75 IU/day compared to the gonadotropin dose used in her previous treatment (e.g.: if 150 IU/d rec FSH was used then 225 IU/d will be used).
Treatment steps:
- Stimulation using an additional 75 IU recombinant FSH per day compared to her previous treatment is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day.
- GnRH antagonist is started at follicle size 12-14 m.
- Trigger is administered once the largest follicle gets >17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval.
- Transfer of 1-2 embryos on day 3 or 5.
- Pregnancy test 12 days after ET.
干预措施: higher dose recFSH (Drug)
结局指标
主要结局
live clinical pregnancy
时间窗: up to 3 months after the embryo transfer; starting with the first patient who has a positive pregnancy test after transfer and up to 3 months after the completion of the study (last transfer with positive result)
intrauterine gestational sac with an embryo with heartbeat at week 10-12
次要结局
- live birth(from up to 9 month after the embryo transfer; starting with the first patient who has a positive pregnancy test after the embryo transfer and up to 8 months after the completion of the study (last transfer with positive result))
研究者
Peter Kovacs MD
medical director Dunamenti REK Istenhegyi IVF Center
Dunamenti REK Istenhegyi IVF Center