In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians. In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of “cancer and fertility preservation”. A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation. Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations.

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Cancer and fertility preservation: international recommendations from an expert meeting

BACKGROUND Successful cryopreservation of oocytes and embryos is essential not only to maximize the safety and efficacy of ovarian stimulation cycles in an IVF treatment, but also to enable fertility preservation. Two cryopreservation methods are routinely used: slow-freezing or vitrification. Slow-freezing allows for freezing to occur at a sufficiently slow rate to permit adequate cellular dehydration while minimizing intracellular ice formation. Vitrification allows the solidification of the cell(s) and of the extracellular milieu into a glass-like state without the formation of ice. OBJECTIVE AND RATIONALE The objective of our study was to provide a systematic review and meta-analysis of clinical outcomes following slow-freezing/thawing versus vitrification/warming of oocytes and embryos and to inform the development of World Health Organization guidance on the most effective cryopreservation method. SEARCH METHODS A Medline search was performed from 1966 to 1 August 2016 using the following search terms: (Oocyte(s) [tiab] OR (Pronuclear[tiab] OR Embryo[tiab] OR Blastocyst[tiab]) AND (vitrification[tiab] OR freezing[tiab] OR freeze[tiab]) AND (pregnancy[tiab] OR birth[tiab] OR clinical[tiab]). Queries were limited to those involving humans. RCTs and cohort studies that were published in full-length were considered eligible. Each reference was reviewed for relevance and only primary evidence and relevant articles from the bibliographies of included articles were considered. References were included if they reported cryosurvival rate, clinical pregnancy rate (CPR), live-birth rate (LBR) or delivery rate for slow-frozen or vitrified human oocytes or embryos. A meta-analysis was performed using a random effects model to calculate relative risk ratios (RR) and 95% CI. OUTCOMES One RCT study comparing slow-freezing versus vitrification of oocytes was included. Vitrification was associated with increased ongoing CPR per cycle (RR = 2.81, 95% CI: 1.05-7.51; P = 0.039; 48 and 30 cycles, respectively, per transfer (RR = 1.81, 95% CI 0.71-4.67; P = 0.214; 47 and 19 transfers) and per warmed/thawed oocyte (RR = 1.14, 95% CI: 1.02-1.28; P = 0.018; 260 and 238 oocytes). One RCT comparing vitrification versus fresh oocytes was analysed. In vitrification and fresh cycles, respectively, no evidence for a difference in ongoing CPR per randomized woman (RR = 1.03, 95% CI: 0.87-1.21; P = 0.744, 300 women in each group), per cycle (RR = 1.01, 95% CI: 0.86-1.18; P = 0.934; 267 versus 259 cycles) and per oocyte utilized (RR = 1.02, 95% CI: 0.82-1.26; P = 0.873; 3286 versus 3185 oocytes) was reported. Findings were consistent with relevant cohort studies. Of the seven RCTs on embryo cryopreservation identified, three met the inclusion criteria (638 warming/thawing cycles at cleavage and blastocyst stage), none of which involved pronuclear-stage embryos. A higher CPR per cycle was noted with embryo vitrification compared with slow-freezing, though this was of borderline statistical significance (RR = 1.89, 95% CI: 1.00-3.59; P = 0.051; three RCTs; I2 = 71.9%). LBR per cycle was reported by one RCT performed with cleavage-stage embryos and was higher for vitrification (RR = 2.28; 95% CI: 1.17-4.44; P =  0.016; 216 cycles; one RCT). A secondary analysis was performed focusing on embryo cryosurvival rate. Pooled data from seven RCTs (3615 embryos) revealed a significant improvement in embryo cryosurvival following vitrification as compared with slow-freezing (RR = 1.59, 95% CI: 1.30-1.93; P < 0.001; I2 = 93%). WIDER IMPLICATIONS Data from available RCTs suggest that vitrification/warming is superior to slow-freezing/thawing with regard to clinical outcomes (low quality of the evidence) and cryosurvival rates (moderate quality of the evidence) for oocytes, cleavage-stage embryos and blastocysts. The results were confirmed by cohort studies. The improvements obtained with the introduction of vitrification have several important clinical implications in ART. Based on this evidence, in particular regarding cryosurvival rates, laboratories that continue to use slow-freezing should consider transitioning to the use of vitrification for cryopreservation.

Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance

Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis.

Background
Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011.

Objectives
To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles.

Search methods
We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). We contacted the authors of eligible studies for missing or unpublished data. The evidence is current to 28 April 2015.

Selection criteria
Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different GnRH agonist versus GnRH antagonist protocols in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Data collection and analysis
Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary review outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Other adverse effects (miscarriage and cycle cancellation) were secondary outcomes. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for each comparison using GRADE methods.

Main results
We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long-course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods.

Live birth

There was no evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I2= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%.

OHSS

GnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I2 = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%.

Other adverse effects

There was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.03, 95% CI 0.82 to 1.29; 34 RCTs, n = 7082, I2 = 0%, moderate quality evidence).

With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I2 = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I2 = 68%; moderate quality evidence).

Authors' conclusions
There is moderate quality evidence that the use of GnRH antagonist compared with long-course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth.

/pdf/gonadotrophin-releasing-hormone-antagonists-for-assisted-3dh7s2nndf.pdf

Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology

https://www.fertstert.org/article/S0015-0282(11)00975-7/pdf

Clinical application of oocyte vitrification: a systematic review and meta-analysis of randomized controlled trials

https://www.huntington.com.br/wp-content/uploads/2013/03/2010.pdf

Prospective randomized comparison of human oocyte cryopreservation with slow-rate freezing or vitrification

https://www.fertstert.org/article/S0015-0282(06)01160-5/pdf

Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in vitro fertilization: a prospective, randomized trial

Successful interval laparoscopic transabdominal cervicoisthmic cerclage preceding twin gestation: a case report.

Purpose
Our purpose was to retrospectively compare controlled ovarian stimulation(COH) in IVF cycles with administration of hCG on the day of menses (D1-hCG) with women not receiving hCG at day 1 of menses (Control).

Human choriogonadotropin prior to controlled ovarian stimulation and in vitro fertilization improves implantation, and pregnancy rates.

An alternate approach to ovulation induction (OI) for IVF: Daily late follicular phase administration of 200 IU hCG − Results of prospective, randomized trial

I.M. Yadid

Papers

Prospective randomized comparison of human oocyte cryopreservation with slow-rate freezing or vitrification

Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in vitro fertilization: a prospective, randomized trial

Successful interval laparoscopic transabdominal cervicoisthmic cerclage preceding twin gestation: a case report.

Human choriogonadotropin prior to controlled ovarian stimulation and in vitro fertilization improves implantation, and pregnancy rates.

An alternate approach to ovulation induction (OI) for IVF: Daily late follicular phase administration of 200 IU hCG − Results of prospective, randomized trial