Routine double-ovarian-stimulation (DuoStim) in poor responders lacks rationale, evidence, and follow-up.

Double ovarian stimulation (DuoStim), initially only suggested for fertility preservation in cancer patients, is now increasingly also used in routine clinical IVF, especially in poor responders. The claimed rational for this is the alleged existence of multiple follicular waves in a single intermenstrual interval, allowing for retrieval of more oocytes in a single IVF cycle. This commentary argues that this expansion of purpose lacks rationale, evidence, and follow-up. Consequently, we suggest that, unless valid clinical indications have been established, DuoStim be only subject of controlled clinical trials with appropriate experimental consents.

Why double ovarian stimulation in an in vitro fertilization cycle is potentially unsafe.

The occurrence of two antral follicle recruitment waves in a single inter-ovulatory interval has been detected in ovaries of normal women. This data supports the claim that a double ovarian stimulation in the same cycle may benefit poor responder patients with an increased recovery of mature oocytes and good quality embryos per single cycle. The double stimulation protocol was the object of several published studies in which, surprisingly, the mechanism and the safety of the double stimulation in the same cycle were poorly addressed. We propose that in the double stimulation protocol, the first stimulation impacts more committed oocytes progenitors ready to differentiate into mature oocytes. Conversely, the protracted exposure of developmentally earlier less-committed ovarian stem cells to FSH, which occurs in the double stimulation protocol, impacts the less differentiated stem cells which take longer to differentiate into oocytes. The proposed mechanism has broad implications for the safety of the double stimulation strategy.

Live birth rate with double ovarian stimulation is superior to follicular phase ovarian stimulation per started cycle in poor ovarian responders.

AIM: To compare the outcome of double ovarian stimulation (DOS) with follicular phase ovarian stimulation (FPS) per started cycle in poor ovarian responders (PORs). METHODS: A total of 204 PORs who underwent ovulation induction for in vitro fertilization, cryopreservation of all embryos available, and frozen embryo transfer cycle were retrospectively analyzed. Of those, 146 received single FPS, and 58 received DOS. All viable embryos were cryopreserved and subsequently transferred within 1-6 months. RESULTS: The number of oocytes collected and the number of mature oocytes per started cycle were higher in the DOS group compared to the FPS group (6.0 ± 1.9 vs. 2.8 ± 1.3 and 4.3 ± 1.3 vs. 2.2 ± 1.2, respectively, p = 0.001). Clinical pregnancy rate and live birth rate per started cycle were also significantly higher in the DOS group than the FPS group (41.4% vs. 16.4% and 36.2% vs. 15.1%, respectively, p < 0.001). The cancellation rate of embryo transfer due to no viable embryo was significantly lower in the DOS group (10.3%) than the FPS group (40.4%) (p = 0.001). In the DOS group, numbers of oocytes (3.2 ± 1.2 vs. 2.7 ± 1.1, p = 0.006), MII oocytes (2.6 ± 1.0 vs. 2.1 ± 0.8, p = 0.001), and cryopreserved blastocysts (1.5 ± 0.8 vs. 1.1 ± 0.7, p = 0.002) were significantly higher in the luteal ovarian stimulation compared to follicular ovarian stimulation. CONCLUSIONS: Live birth per started cycle with DOS is superior to FPS in PORs. Luteal phase stimulation contributes to improving pregnancy rates in these patients.

How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis.

PURPOSE: To compare the effectiveness of starting the ovarian stimulation on the early follicular phase ("Conventional") with the newer range of non-conventional approaches starting in the luteal phase ("Luteal"), random-start, and studies implementing them in DuoStim ("Conventional"+"Luteal"). METHODS: Systematic review. We searched CENTRAL, PubMed, and Embase, on March 2020. We included randomized and non-randomized controlled trials that compared "Luteal," random-start ovarian stimulation or DuoStim with "Conventional"; we analyzed them by subgroups: oocyte freezing and patients undergoing ART treatments, both, in the general infertile population and among poor responders. RESULTS: The following results come from a sensitivity analysis that included only the low/moderate risk of bias studies. When comparing "Luteal" to "Conventional," clinically relevant differences in MII oocytes were ruled out in all subgroups. We found that "Luteal" probably increases the COH length both, in the general infertile population (OR 2.00 days, 95% CI 0.81 to 3.19, moderate-quality evidence) and in oocyte freezing cycles (MD 0.85 days, 95% CI 0.53 to 1.18, moderate-quality evidence). When analyzing DuoStim among poor responders, we found that it appears to generate a higher number of MII oocytes in comparison with a single "Conventional" (MD 3.35, 95%CI 2.54-4.15, moderate-quality evidence). CONCLUSION: Overall, this systematic review of the available data demonstrates that in poor responders, general infertile population and oocyte freezing for cancer stimulation in the late follicular and luteal phases can be utilized in non-conventional approaches such as random-start and DuoStim cycles, offering similar outcomes to the conventional cycles but potentially with increased flexibility, within a reduced time frame. However, more well-designed trials are required to establish certainty.

Triple stimulation (TriStim) before bilateral oophorectomy in a young woman with ovarian cancer: a case report and review of the literature.

BACKGROUND: Double ovarian stimulation (DuoStim) involves two rounds of controlled ovarian stimulation (COS) and oocyte retrieval in immediate succession. It represents a promising approach to increase oocyte yield for patients with diminished ovarian reserve or those with limited time before fertility-threatening oncologic treatment. We report the case of a 31-year-old woman with Stage IC endometrioid ovarian cancer who underwent a triple stimulation or "TriStim," completing three rounds of COS and oocyte retrieval within 42 days prior to bilateral salpingo-oophorectomy. CASE PRESENTATION: A 31 year old nulligravid woman presented for fertility preservation counseling following a bilateral ovarian cystectomy that revealed Stage IC endometroid adenocarcinoma arising within endometrioid borderline tumors. The patient was counseled for bilateral salpingo-oophorectomy, lymph node dissection, and omentectomy followed by three cycles of carboplatin/paclitaxel. Prior to this, all within six weeks, the patient underwent three rounds of controlled ovarian stimulation using an antagonist protocol and human chorionic gonadotropin (hCG) trigger, resulting in vitrification of nine two-pronuclear zygotes (2PN), after which definitive surgery was performed. CONCLUSIONS: Advantages of DuoStim procedures are increasingly recognized, especially for oncology patients with limited time before potentially sterilizing cancer treatment. To our knowledge, this is the first report of a triple stimulation ("TriStim"). Our case highlights that triple stimulation is a viable option for patients needing urgent fertility preservation in order to maximize egg and embryo yield within a limited time period.

DuoStim - a reproducible strategy to obtain more oocytes and competent embryos in a short time-frame aimed at fertility preservation and IVF purposes. A systematic review.

Recent evidence suggests that follicular development occurs in a wave-like model during the ovarian cycle, where up to three cohorts of follicles are recruited to complete folliculogenesis. This understanding overtakes the previous dogma stating that follicles grow only during the follicular phase of the menstrual cycle. Therefore, in in vitro fertilization (IVF), novel protocols regarding ovarian stimulation have been theorized based on the use of gonadotrophins to prompt the growth of antral follicles at any stage of the menstrual cycle. These unconventional protocols for ovarian stimulation aim at a more efficient management of poor-prognosis patients, otherwise exposed to conflicting outcomes after conventional approaches. DuoStim appears among these unconventional stimulation protocols as one of the most promising. It combines two consecutive stimulations in the follicular and luteal phases of the same ovarian cycle, aimed at increasing the number of oocytes retrieved and embryos produced in the short time-frame. This protocol has been suggested for the treatment of all conditions requiring a maximal and urgent exploitation of the ovarian reserve, such as oncological patients and poor responders at an advanced maternal age. At present, data from independent studies have outlined the consistency and reproducibility of this approach, which might also reduce the drop-out between consecutive failed IVF cycles in poor-prognosis patients. However, the protocol must be standardized, and more robust studies and cost-benefit analyses are needed to highlight the true clinical pros and cons deriving from DuoStim implementation in IVF.

Contribution of rescue in-vitro maturation versus double ovarian stimulation in ovarian stimulation cycles of poor-prognosis women.

RESEARCH QUESTION: Maximizing the number of oocytes and embryos obtained in the shortest possible time is of considerable potential clinical significance for women with poor prognosis. The aim of this study was to develop a clinically applicable strategy to obtain more oocytes and viable embryos in one menstrual cycle for poor-prognosis women. DESIGN: Prospective cohort study of 146 women with poor prognosis who received rescue in-vitro maturation (IVM) (n = 50) or double ovarian stimulation (DuoStim) (n = 96) between December 2015 and February 2018. Outcomes, number of oocytes retrieved and matured, and embryo developmental potential were compared between the two groups. RESULTS: The rates of mature oocytes, available embryos and top-quality embryos from luteal phase stimulation (LPS) of DuoStim were all significantly higher than those derived from the immature oocytes of rescue IVM (P < 0.05). The relative contributions of LPS in the DuoStim group for proportion of mature oocytes, available embryos and top-quality embryos were all significantly higher than IVM in the rescue IVM group (P < 0.001). The overall cancellation rate of no oocyte or available embryo significantly decreased from 30.21% to 9.38% (P < 0.001) when DuoStim was carried out, which decreased from 24.00% to 12.00% with no significant difference in the rescue IVM group when immature sibling oocytes were matured in vitro. CONCLUSION: Rescue IVM and DuoStim can contribute more competent oocytes and viable embryos in the shortest possible time for poor-prognosis women, of which DuoStim may be more efficient.

Random-start ovarian stimulation with aromatase inhibitor for fertility preservation in women with Japanese breast cancer.

PURPOSE: Fertility preservation is an important issue for young cancer patients. Random-start controlled ovarian stimulation and double ovarian stimulation have been proposed for efficient oocyte retrieval within the limited time before cancer therapy. We aimed to clarify the efficacy of these new protocols within the Japanese population. METHODS: We performed a retrospective observational study at a multicenter from February 2012 to August 2017. The study entailed 50 cycles with 34 patients who underwent fertility preservation due to breast cancer. Follicular phase or luteal phase ovarian stimulation with aromatase inhibitor was performed. A second ovarian stimulation was started with or without waiting until the next menstruation. We measured the number of retrieved oocytes and cryopreserved oocytes/embryos, the ratio of mature oocytes, and the fertilization rate. RESULTS: The numbers of retrieved oocytes and frozen oocytes/embryos were not significantly different between follicular phase and luteal phase ovarian stimulation. The number of retrieved oocytes was not reduced at the second ovum pick up compared to the first ovum pick up in the double ovarian stimulation. CONCLUSIONS: Random-start controlled ovarian stimulation and double ovarian stimulation with aromatase inhibitor for breast cancer patients were effective protocols for retrieving a greater number of oocytes within the limited time.

Double ovarian stimulation during the follicular and luteal phase in women ≥38 years: a retrospective case-control study.

Previous studies have shown that double ovarian stimulation could obtain more oocytes in women with poor ovarian response. This retrospective case-control study aimed to investigate the efficacy of double ovarian stimulation in older women. One hundred and sixteen women aged ≥38 years who received double ovarian stimulation were assigned to the study, with 103 divided into four groups according to follicular-phase ovarian stimulation protocols, including gonadotrophin-releasing hormone agonist short protocol (n = 27), gonadotrophin-releasing hormone antagonist protocol (n = 32), mild stimulation protocol (n = 21) and medrocyprogesterone acetate (MPA) pituitary down-regulation protocol (n = 23). Numbers of oocytes retrieved and available embryos after double ovarian stimulation were more than double those obtained after follicular-phase ovarian stimulation alone. In total 81.90% of patients had available embryos, and the cancellation rate decreased from 37.07% to 18.10%. Forty-eight cases underwent 50 cryopreserved embryo transfer cycles, with a 22.00% clinical pregnancy rate. The implantation rate (10.53% versus 10.67%) was similar between the embryos derived from first and second stimulations. The results suggest that double ovarian stimulation could increase the chances of achieving pregnancy by accumulating more oocytes/embryos in a short time, which might serve as a useful strategy for older women.