Marta Devesa

Concise Review: Fertility Preservation: An Update

Fertility preservation is an emerging field in medicine that enables men, women, and children to maintain reproductive health when it is threatened by gonadotoxic treatment. Patients affected by other nononcologic malignancies that can impair spermatogenesis and ovogenesis can also benefit from fertility preservation treatments. Age‐related infertility can also be overcome by cryopreserving gametes or embryos. The only established methods for fertility preservation in male patients are sperm cryopreservation in postpubertal age and experimental testicular tissue cryopreservation in prepubertal age. In adult women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Fertility preservation treatments must be addressed through a multidisciplinary approach that involves gynecologists, urologists, oncologists, pediatricians, and professionals in the field of medically assisted reproduction to work in coordination to provide patients with counseling and comprehensive information about fertility issues.

Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes

OBJECTIVE To assess the clinical pregnancy rate per transfer in recipients of embryos from donor oocytes obtained after ovarian stimulation initiated on day 2 (D2) or day 15 (D15) of the menstrual cycle with a secondary end point of comparing the response to stimulation. DESIGN Prospective observational comparative study. SETTING Private in vitro fertilization (IVF) program. PATIENT(S) Oocyte donors (OD) and recipients. INTERVENTION(S) Donors stimulated within 3 months, starting on day 2 or day 15 after bleeding, with recombinant follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) antagonist, and GnRH agonist trigger, and oocytes vitrified and later assigned to recipients, followed by routine IVF procedures one to two embryos transferred. MAIN OUTCOME MEASURE(S) Primary outcome pregnancy rate, and secondary outcome number of mature oocytes retrieved. RESULT(S) Nine D2 and nine D15 cycles were performed in nine donors. There were no differences between D2 and D15 in the number of mature oocytes obtained (14.0±6.96 vs. 16.89±7.52). To date, 20 recipients have received vitrified oocytes (8 recipients received D2 oocytes and 12 recipients received D15 oocytes). There were no differences between the groups of recipients in fertilization rate (77.3% vs. 76.5%) or number of embryos transferred (1.50±0.53 vs. 1.67±0.65). Twelve clinical pregnancies were obtained. No differences were noted in pregnancy rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%) between recipients of D2 oocytes and recipients of D15 oocytes. CONCLUSION(S) Donor oocytes obtained after ovarian stimulation initiated on day 15 of the cycle achieve good pregnancy rates. This information is useful for patients with cancer undergoing fertility preservation. CLINICAL TRIAL REGISTRATION NUMBER NCT 01645241.

Cancer and fertility preservation: Barcelona consensus meeting

Abstract Improvements in early diagnosis and treatment strategies in cancer patients have enabled younger women with cancer to survive. In addition to the stressful event of the diagnosis, patients with malignant diseases face the potential loss of the opportunity to have children. Preservation of fertility has become a challenging issue and it is still surrounded by controversies. On the basis of available evidence, a group of experts reached a consensus regarding the options for trying to preserve fertility in women with cancer: among established methods, in postpubertal women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Combining several strategies on an individual basis may improve the chances of success. Realistic information should be provided before any intervention is initiated. Counseling should offer support for patients and provide better care by understanding emotional needs, psychological predictors of distress and methods of coping. Early referral to the fertility specialist is essential as fertility preservation (FP) may improve quality of life in these patients. The information summarized here is intended to help specialists involved in the treatment of cancer and reproductive medicine to improve their understanding of procedures available for FP in young cancer patients.

Live birth using vitrified-warmed oocytes in invasive ovarian cancer: case report and literature review

This article reports the live birth of a healthy newborn using vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after insemination of warmed oocytes. Eighteen days after the transfer, she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. As far as is known, this is the first live birth reported through vitrified-warmed oocytes in a patient with invasive ovarian cancer. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, controversial issues are discussed. Fertility preservation is a proven possibility in some cancer patients according to their age, disease and time available until the beginning of their oncological treatment. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, no live birth has been reported. We report the live birth of a healthy newborn through vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after the insemination of the warmed oocytes. Eighteen days after the transfer she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. To our knowledge, this is the first live birth reported using vitrified-warmed oocytes in invasive ovarian cancer. Controversial issues are reviewed and discussed.

Combined strategy for fertility preservation in an oncologic patient: vitrification of in vitro matured oocytes and ovarian tissue freezing

Breast cancer is the most common malignancy in women and nearly 7% of cases are diagnosed before age 40 [1]. Diagnosis at early ages is associated with a worse prognosis and therefore, these cases are usually managed with adjuvant chemotherapy and/or hormonal therapy. These treatments are effective in reducing recurrence rates and improving survival rates; however, they have a negative impact on ovarian function and fertility [2]. Fertility preservation in these cases may be of interest also due to the current trend towards delaying motherhood, which leads to a situation where many women may have not fulfilled their motherhood desire at the time of breast cancer diagnosis. There are several strategies to preserve fertility. Choosing one or the other will depend on patient’s age, tumour biology and, above all, time availability until the start of gonadotoxic treatment.

Should progesterone on the human chorionic gonadotropin day still be measured

OBJECTIVE To evaluate in our setting whether there is currently a level of P on the hCG day (P-hCG) predictive of no pregnancy. DESIGN Observational study of prospectively collected data of the P-hCG levels of stimulated IVF cycles. SETTING In vitro fertilization unit. PATIENT(S) All cycles of IVF/intracytoplasmic sperm injection with fresh embryo transfer performed between January 2009 and March 2014. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pregnancy rate. RESULT(S) Clinical pregnancy rate per ET was 38.7% and live birth rate was 29.1%. The P-hCG concentration was positively correlated to E2 on the hCG day, and the number of oocytes was negatively correlated to age. Progesterone on hCG day was higher among agonist- compared with antagonist-treated patients (mean ± SD: 1.13 ± 0.69 ng/mL vs. 0.97 ± 0.50 ng/mL) and among recombinant FSH compared with recombinant FSH + hMG stimulation (mean ± SD: 1.11 ± 0.58 ng/mL vs. 0.94 ± 0.50 ng/mL). Pregnancy rate was positively associated with the number of oocytes. There was no correlation between P-hCG value and pregnancy rate, overall or according to the type of treatment. CONCLUSION(S) In our setting there is no P-hCG value differentiating a good from a poor cycle success rate. CLINICAL TRIAL REGISTRATION NUMBER NCT02323347.

Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol.

Objective. To determine the efficacy of the flare-up agonist and the antagonist protocols in patients with poor prognosis for ovarian response. Methods. A randomised trial was conducted on two hundred and twenty-one women considered as having poor prognosis for ovarian response to stimulation, based on previous cycles or clinical criteria. All women were prospectively randomised into two groups of treatment (flare-up group and antagonist group) by computer-assisted randomisation in a 1:1 ratio. The main outcome measure was clinical pregnancy rate. Results. Groups were homogeneous in age and baseline characteristics. Duration of stimulation, gonadotropin consumption, number of oocytes retrieved and number and quality of embryos transferred did not differ significantly between the groups. E2 level the day of hCG administration was significantly higher in the flare-up group. Pregnancy rates per started cycle were 15% in the flare-up group and 14.1% in the antagonist group. Cancellation rates were 12.5% in the flare-up group and 16.3% in the antagonist group. None of these differences reached statistical significance. Conclusions. No statistically significant differences were observed between the two protocols regarding clinical pregnancy rates. In patients with poor prognosis for ovarian response, the flare-up agonist and the antagonist protocols were comparable regarding clinical pregnancy rates.

Linking back-to-back stimulation cycles with oral contraceptives or progestins in women undergoing embryo accumulation for preimplantation genetic testing, a retrospective study

Abstract This retrospective study was carried out to determine which strategy is associated with improved outcomes in two back-to-back cycles when undergoing embryo accumulation. Eighty patients with two stimulation cycles performed with <45 days between retrievals between Jan’16-Mar’17 were included. Patients were segregated according to the strategy used to link stimulations: spontaneous menses (SM), vaginal micronized progesterone (VMP) or oral contraceptive pills (OCP). Main outcome measure was oocytes retrieved. The oocytes retrieved difference between cycles was −0.9 in SM, −1.5 in VMP and +0.4 in OCPs. Although not statistically significant, more oocytes retrieved were observed in the 2ndcycle when OCPs were used (9.0 ± 3.7 vs. 9.4 ± 4.1)? whereas fewer oocytes retrieved were observed when SM (9.4 ± 3.9 vs. 8.5 ± .0) or VMP (9.8 ± 5.7 vs. 8.2 ± 4.4) were used. After adjusting for age, gonadotropins and stimulation days (2nd cycle) and treatment group in an ANCOVA model, no treatment was associated with a higher average number of oocytes retrieved (power: 14.9%) or a higher difference of oocytes retrieved (power: 22.3%). Although no statistical significance was reached, OCPs were observed to achieve higher average and positive difference of oocytes retrieved in the 2nd cycle. 摘要 本项回顾性研究旨在确定在接受胚胎积累女性的两个连续刺激周期中, 哪种策略与改善结局相关。经检索在1月16日至3月17日之间进行两次＜45天刺激周期的患者共有80例。根据不同刺激策略对患者进行以下分组：自发性月经（spontaneous menses, SM）、阴道微粒化黄体酮（vaginal micronized progesterone, VMP）和口服避孕药（oral contraceptive pills, OCP）。主要观察指标为获卵数。周期间获卵数的差异在SM组为-0.9, VMP组为-1.5, OCPs组为+0.4。尽管没有统计学意义, 但OCPs组在第2周期中可观察到更多的获卵数（9.0±3.7和9.4±4.1）；相反, SM组（9.4±3.9和8.5±.0）和VMP组（9.8±5.7和8.2±4.4）则观察到相对较少的获卵数。在协方差分析模型中, 调整年龄、促性腺激素及刺激天数（第2周期）和治疗组后, 未发现不同治疗与高平均获卵数（power：14.9%）或获卵数存在明显差异（power：22.3%）相关。尽管未达到统计学意义, 但观察到OCPs组在第2周期中平均获卵数和阳性差异更高。

Inconclusive results in preimplantation genetic testing: go for a second biopsy?

Abstract The transition in biopsy timing from blastomere to trophectoderm biopsy has led to a remarkable decrease in the percentage of undiagnosed blastocysts. However, patients with few or no euploid blastocysts can be affected by this residual percentage of diagnosis failure. The aim of this study is to assess whether blastocyst rebiopsy and revitrification is an efficient and safe procedure to be applied in cases of no results after analysis. Fifty-three patients agreed to the warming of 61 blastocysts to perform a second biopsy and PGT-A by aCGH. Only 75.4% of the blastocysts survived, reexpanded, and could be rebiopsied. After the second biopsy and analysis, 95.6% of the blastocysts were successfully diagnosed with an euploidy rate of 65.9%. Eighteen euploid blastocysts were warmed and transferred to 18 patients with a 100% survival and reexpansion rate. Seven clinical pregnancies have been achieved with 4 live births, 1 ongoing pregnancy, and 2 miscarriages. Thus, although few transfers of rebiopsied and revitrified blastocysts have been performed till date, our preliminary results show that this approach is efficient and safe to be applied for undiagnosed blastocysts, as it ultimately allows the transfer of euploid blastocysts and good clinical outcomes.

Luteal-Phase Stimulation

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]).