Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive technology.

OBJECTIVE: To assess the impact of 3 different ovarian stimulation protocols on surrogate biomarkers of coagulation. DESIGN: Observational multicenter cohort study. SETTING: The study was conducted in assisted reproductive technology (ART) units. PATIENTS: Infertile women undergoing ART in 2017-2019 were included. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Our primary outcome was the endogenous thrombin potential (ETP) assessed by the calibrated automated thrombogram. The ETP was measured at baseline (T1), on the day of ovulation triggering (T2), and 7 days after triggering (T3). Three protocols were prescribed according to the standards used and without hormonal before treatment: agonist protocol with human chorionic gonadotropin (hCG) trigger (ag-hCG), antagonist protocol with hCG trigger (atg-hCG), or GnRH agonist trigger. The evolution of ETP was compared among groups using a mixed-effects linear regression model. RESULT(S): Sixty-four women with a mean age of 37.8 years participated in the study: of which 24, 16, 24 received ag-hCG, atg-hCG, and GnRH agonist triggers, respectively. As expected, the mean serum estradiol levels in GnRH agonist trigger were statistically higher at T2 and lower at T3 than that for both ag-hCG and atg-hCG. Overall, the ETP evolution over time was statistically different between the groups. Values were similar between groups at T1 and increased at T2 in each group. The greatest difference occurred between T2 and T3 in each group. The ETP continued to increase at T3 in ag-hCG (+110 nM/L × min) and atg-hCG (+171 nM/L × min), but it remained stable in GnRH agonist trigger (-2 nM/L × min). Sex hormone-binding globulin showed persistent increase at T3 despite the fall in estradiol levels, particularly in the GnRH agonist trigger group. CONCLUSION(S): The ag-hCG and atg-hCG groups were associated with a higher hypercoagulable state at T3 than the GnRH agonist trigger group. However, our results show the persistence of a hypercoagulable state after the GnRH agonist triggering despite a sharp drop in estradiol levels. These findings may support the use of GnRH agonist trigger protocol in patients with high thrombotic risk and gives new insight into the fact that coagulation parameters could be disturbed for long time periods. CLINICAL TRIAL REGISTRATION NUMBER: NCT04188444.

Testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys: A 6 year experience from a Swiss multi-center network.

Testicular tissue cryopreservation is the only option of fertility preservation in prepubertal boys. While it is considered experimental, since procedures to obtain mature spermatozoa from prepubertal testicular tissue are still under development, testicular tissue cryopreservation programs have emerged worldwide. Our aim was to study the feasibility and safety of a program of testicular tissue cryopreservation in prepubertal and adolescent boys facing gonadotoxic treatment in three University hospitals in Switzerland. Testicular tissue cryopreservation was accepted by 90% of families, with a total of 35 patients included. The average patient age was 8.5 years (range 7 months to 18.5 years). Malignancies were the most common diagnosis (31 patients, 88.6%) with 16 (45.7%) solid tumors and 15 (42.9%) hematological malignancies. Four (11.4%) patients had a benign condition. The main indication for testicular tissue cryopreservation was conditioning for hematologic stem cell transplantation (25 patients, 71.4%). Testicular tissue was cryopreserved according to the freezing protocol of Louvain Catholic University (Belgium), which includes either only immature testicular tissue freezing, or mature and immature testicular tissue freezing depending on the age of the patient and the presence or absence of haploid cells. The median number of spermatogonia per tubule cross-section was 2 (range 0-6) and spermatozoa were found in only one patient. Tumoral cells were found in one testicular biopsy of a leukemic patient. There were two minor adverse events and none of them required medical treatment or surgical revision. Five patients died during follow-up. Our data demonstrate the feasibility and safety of a program of testicular tissue cryopreservation coordinated by a multidisciplinary team of fertility preservation. Despite the experimental aspect of the procedure, the acceptation rate was high, which highlights the willingness of families and patients to participate in testicular tissue cryopreservation.

Successful in vivo retrieval of oocytes after ovarian stimulation for fertility preservation before oophorectomy by laparotomy for a young patient with ovarian cancer: Case report and review of literature.

OBJECTIVE: To report a case of direct in vivo oocytes retrieval for fertility preservation before oophorectomy by open surgery in a young patient with ovarian cancer. DESIGN: case report and literature review. SETTING: University hospital. PATIENTS: A 29-year-old nulliparous patient, recently diagnosed with low grade serous ovarian carcinoma.The patient consented to the removal of her remaining ovary but wished to preserve oocytes and declined hysterectomy. Conventional trans-vaginal US-guided oocyte retrieval was contra-indicated because of the risk of malignant cell dissemination to the abdomen and the vaginal puncture sites. INTERVENTIONS: Controlled ovarian stimulation with gonadotrophins was realized. Comprehensive surgical staging was performed 35 h after ovulation triggering using rHCG. The oocytes retrieval was performed in vivo with ultrasound guidance at time of laparotomy before oophorectomy without any time of ischemia. RESULTS: Seven mature oocytes were obtained and vitrified. CONCLUSIONS: This case highlights the feasibility of in vivo oocytes retrieval of mature oocytes during open surgery for gynecologic cancers. By avoiding transvaginal follicular retrieval, the risk of malignant cell contamination to vaginal and parametrial tissues is reduced, limiting cancer upstaging.

Hypergonadotropic hypogonadism after ovarian tissue cryopreservation on a 13-year-old female: A case report and review of the literature.

Ovarian failure is a major long-term adverse event following gonadotoxic treatment of malignant diseases. Ovarian tissue cryopreservation can be offered in some conditions to preserve fertility. We report the case of a 13-year-old female with a diagnosis of acute myeloid leukemia, who presented with hypergonadotropic hypogonadism after unilateral ovariectomy for fertility preservation and before highly gonadotoxic treatment. Even though damage seemed only partial, this case suggests that the remaining contralateral ovarian function may be compromised after ovarian tissue cryopreservation, leading per se to a hypergonadotropic hypogonadism. Although indication of ovarian cryopreservation is not called into question in situations of highly gonadotoxic therapy, this procedure should only be performed after evaluation by a specialized multidisciplinary team and provided a solid indication.

Use and Effectiveness of Sperm Cryopreservation for Adolescents and Young Adults: A 37-Year Bicentric Experience.

Aim: Sperm cryopreservation (SCP) should be offered to every adolescent before gonadotoxic treatment, but experience in this age range is still relatively limited. The goal of this study is to assess how to optimize this procedure. Methods and Patients: One hundred thirty-three patients between 12 and 20 years old, who underwent SCP between 1980 and 2017, were included. Baseline data (age, indication for SCP, and semen parameters at freezing) and follow-up data (outcome of sperm straws and follow-up of sperm quality) were collected and analyzed. Results: SCP is feasible from the age of 12. Semen assessment parameters at this age were close to parameters of adults. However, we observed quantitative impairments in testicular tumors and qualitative impairments in leukemia and bone marrow failure. Four patients (3%) used their cryopreserved semen for medically assisted reproduction, 15 patients died (11.3%), 18 asked for destruction of their straws (13.5%), and nine samples were destroyed because of lack of news (6.8%). Very few patients underwent a sperm analysis after treatment. Conclusions: SCP is an efficient, still underused, procedure for adolescents and young adults. Cryopreserved sperm is rarely used and rarely destroyed, but studies with a longer follow-up are needed to better assess these observations. Follow-up with a specialist of reproductive medicine is valuable for better information of the patient.

The effect of mind-body interventions on psychological and pregnancy outcomes in infertile women: a systematic review.

Preliminary evidence suggests that mind-body interventions, including mindfulness-based interventions and yoga, may be effective in reducing mental health difficulties and psychological distress in infertile patients undergoing fertility treatments. We systematically reviewed and synthesized current medical literature of the effectiveness of mind-body interventions in reducing the severity of psychological distress and improving marital function and pregnancy outcomes in infertile women/couple. Databases including PsychINFO, PubMed, EMBASE, and the Cochrane Library were searched for relevant studies. Manual searches were conducted in relevant articles. We included 12 studies that met the inclusion criteria. Four studies were randomized controlled trials (RCT), 4 non-randomized controlled trial (NRCT), and 4 uncontrolled studies (UCT). Participation in a mind-body intervention was associated with reduced anxiety trait and depression scores. The reduction was of low or moderate amplitude in most studies. Our review offers evidence for the effectiveness of mind-body interventions in reducing anxiety state and depression in infertile women and a possible improvement in pregnancy rate. Further RCTs with a precise timing of intervention are needed.

Impact of letrozole supplementation during ovarian stimulation for fertility preservation in breast cancer patients.

OBJECTIVES: Oocyte and/or embryo vitrification after controlled ovarian stimulation (COS) represents the most established method of fertility preservation (FP) before cancer treatment. However, traditional COS regimens are associated with supraphysiologic serum estradiol and are therefore not recommended in estrogen-sensitive diseases such as breast cancer (BC). To protect the patients from the potential deleterious effects of elevated estrogen levels during COS for FP, protocols using aromatase inhibitors (letrozole) were developed. The present study aims at investigating whether COS with letrozole supplementation (COSTLES) modifies ovarian response in BC patients. STUDY DESIGN: One hundred and seventy-seven BC patients candidates for FP using oocyte and/or embryo vitrification following COS referred to our center between July 2013 and December 2016 were included in this retrospective case-control study. 94 patients underwent COSTLES while 83 had standard GnRH antagonist protocol. The number of oocytes retrieved, oocyte maturation rates, number of oocytes vitrified and follicle responsiveness to FSH assessed by the Follicular Output Rate (FORT) were assessed. RESULTS: Women in both groups were comparable in terms of age and ovarian reserve tests leading to a similar number of oocyte recovered (13.1 ± 10.0 vs. 12.2 ± 8.0 oocytes, respectively, NS). However, oocyte maturation rates were significantly lower in COSTLES compared to standard protocol (64.9 ± 22.8 vs. 77.4 ± 19.3%, p < 0.001). As a result, the number of mature oocyte vitrified was lower in COSTLES group (7.8 ± 5.3 vs. 10.3 ± 8.5 oocytes, p < 0.001 respectively). CONCLUSION: Despite similar response to exogenous FSH, BC patients having undergone COSTLES show reduced oocyte maturation rates in comparison with those having received standard stimulation regimen.

[Preimplantation genetic testing]. / Gynécologie-obstétrique: Tests préimplantatoires de l'embryonen médecine de reproduction.

Preimplantation genetic testing avoids the transmission of monogenic diseases or structural chromosome abnormality to the offspring in fertile couples. Furthermore, it allows screening for aneuploidies (PGT-A, Preimplantation genetic testing for aneuploidy), with the aim of selecting one euploid embryo before transfer in infertile couples undergoing in vitro fertilization (IVF). Indeed, aneuploidies are frequent and explain most IVF failures and early miscarriages. The indications for PGT-A remain controversial, due to the lack of clear evidence of improved outcomes after IVF. Cost-effectiveness studies and follow-up of neonatal outcomes are needed. Finally, each situation requires counseling taking into account ethical considerations.

Les tests préimplantatoires permettent à un couple fertile d'éviter la transmission d'une maladie monogénique ou d'une anomalie chromosomique structurelle à sa descendance. Mais ils peuvent également dépister des aneuploïdies (PGT-A, Preimplantation genetic testing for aneuploidy), avec pour but la sélection d'un embryon euploïde avant transfert in utero pour les couples infertiles réalisant une fécondation in vitro (FIV). En effet, les aneuploïdies, très fréquentes, sont à l'origine de la majorité des échecs d'implantation après FIV et des avortements spontanés précoces. Les indications du PGT-A restent néanmoins controversées en l'absence de preuve évidente d'une amélioration des résultats en FIV. Des études coût/efficacité et un suivi des issues néonatales sont nécessaires. Enfin, chaque situation nécessite un counseling en intégrant les aspects éthiques.

Comparison of GnRH agonist and hCG for priming in vitro maturation cycles in cancer patients undergoing urgent fertility preservation.

In vitro maturation (IVM) of oocytes retrieved at germinal vesicle or Metaphase I stage, followed by vitrification of Metaphase II (MII) oocytes, has recently emerged as an option for urgent fertility preservation (FP). Priming is usually achieved with an injection of hCG, 10,000 IU, 36 hours before retrieval. This study aimed to assess a new method of priming, using GnRH agonists, and compare it to hCG, in cancer patients undergoing urgent FP. From 2009 to 2015, 373 cancer patients underwent MII oocyte cryopreservation after IVM cycles primed either with GnRHa (triptorelin 0.2 mg) (n = 138) or hCG (10,000 IU) (n = 235). Patients' characteristics were comparable between the two groups. The number of COC retrieved was significantly higher in the GnRHa group (9.1 ± 6.8 versus 7.7 ± 5.5 oocytes, p = 0.04). However, the maturation rates (59 ±25% versus 64 ±26%, p = 0.07, respectively), and the total number of MII oocytes frozen (5.2 ±4.2 versus 4.9 ±4.0, p = 0.6, respectively) were similar between the GnRha and hCG groups. We did not find any difference between GnRHa and hCG priming for IVM. GnRHa priming is more physiological since it stimulates endogenous FSH and LH activity, and is well suited for FP in hormone-sensitive cancers and urgent cases.

Shedding light on the fertility preservation debate in women with endometriosis: a swot analysis.

Endometriosis, a hormone-dependant condition affecting around 10% of women in their reproductive years, has frequent consequences on fertility. Indeed, a proportion of women will require assisted reproductive techniques or surgery in order to achieve pregnancy. Recent refining of stimulation protocols and vitrification techniques has created new possibilities in the field of fertility preservation. As a consequence, oocyte vitrification is now discussed not only in oncologic situations, but also in other conditions at risk of altered ovarian reserve and poor fertility outcome. In endometriosis, various mechanisms can impair ovarian function and diminish ovarian, particularly bilateral or repeated cystectomy. Fertility preservation could represent an option for women with endometriosis but still remains controversial. In order to shed some light on this complex subject and to outline different issues at stake we conducted a SWOT analysis highlighting strengths, weaknesses, opportunities and threats of oocyte vitrification in women with endometriosis.

Fertility Preservation in Endocrine Disorders during Transition for Girls.

Recent advances in fertility preservation (FP) techniques have led to a wide spread of indications. FP should now be discussed not only for young girls having to receive gonadotoxic treatments for cancer, but also for those with genetic or endocrine disorders, as well as benign ovarian diseases at risk of premature ovarian insufficiency. For premenarchal girls, ovarian tissue cryopreservation is still the only available technique. Oocyte cryopreservation after ovarian stimulation could be offered to postmenarchal girls. Whenever possible, the parents and the young patient should be informed of the benefits to be expected, as well as of the risks and limits of FP for children.

[Fertility and cancer in young adults : cured, but what about having children ?] / Fertilité et cancer chez les jeunes adultes : guéri, mais pourrais-je avoir des enfants ?

Every year, cancer affects more than a million adolescents and young adults (AYA) in high-income countries. AYA patients represent a heterogeneous but distinct population, aged from 15 to 39 (-45) years old, among which different types of cancer are found compared to the ones affecting children and older adults. Although these pathologies remain the leading cause of death in the AYA age range, the survival rate in this population has significantly improved in recent years, averaging 85%. The aim of this article is to review one major issue in AYA survivors, which is the risk of impaired fertility due to oncological treatments, and the different strategies available to address this problem.

Chaque année, le cancer touche plus d'un million de jeunes adultes (AJA) dans les pays à revenus élevés. Les AJA représentent une population hétérogène mais distincte de patients, âgés de 15 à 45 ans, chez lesquels on retrouve des cancers qui diffèrent de ceux rencontrés chez les enfants ou les personnes plus âgées. Quoique ces pathologies restent la première cause de mortalité dans cette tranche d'âge, la survie de ces patients s'est considérablement améliorée ces dernières années avec un taux de guérison atteignant 85 %. Cet article a pour but d'aborder une question d'importance majeure chez les survivants en âge de procréer, à savoir le risque d'altération de la fertilité lié aux traitements oncologiques, ainsi que les différentes stratégies à disposition pour pallier cette problématique.

[Hormonal treatments and venous thrombosis in women]. / Traitements hormonaux et risque de thrombose veineuse chez la femme.

Venous thromboembolism is frequently associated with hormonal factors in women. A thorough medical history taking of vascular risks and an individual evaluation of the risk-benefit ratio should precede any prescription of hormonal therapies. In contrary to progestin-only-pills, estroprogestative contraceptives increase 3-6 times the risk of venous thrombosis. In assisted reproductive techniques, venous thrombosis is frequently associated with the occurrence of a severe ovarian hyperstimulation syndrome. Antagonist ovarian stimulation protocols lower the risk of hyperstimulation and should therefore be preferred. Finally, at menopause, hormonal treatments combining transdermal estradiol and micronized progesterone do not seem to increment the risk of thrombosis.

La maladie veineuse thromboembolique est fréquemment associée aux facteurs hormonaux chez la femme. La prescription de toute thérapeutique hormonale sera précédée d'un interrogatoire minutieux à la recherche de facteurs de risque vasculaires et d'une évaluation individuelle de la balance bénéfice-risque. Contrairement à la contraception micro-progestative, la contraception œstroprogestative augmente le risque de thrombose veineuse de 3 à 6 fois. En procréation médicalement assistée, la thrombose veineuse est fréquemment associée à la survenue d'un syndrome d'hyperstimulation ovarienne sévère. Les protocoles de stimulation antagonistes minimisant le risque d'hyperstimulation ovarienne sont donc à privilégier. Enfin, après la ménopause, le traitement hormonal associant de l'œstradiol par voie percutanée et de la progestérone micronisée ne semble pas augmenter le risque de thrombose veineuse.

Freezing oocytes or embryos after controlled ovarian hyperstimulation in cancer patients: the state of the art.

Quality of life of young cancer survivors has become a major issue. However, anticancer therapies can have a detrimental impact on fertility. It is now well-established that all patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available. Currently, oocyte or embryo banking after controlled ovarian hyperstimulation represents the most effective method for preserving female fertility. Over the past years innovative protocols of ovarian stimulation have been developed to enable cancer patients to undergo oocyte or embryo cryopreservation irrespective of the phase of the cycle or without exogenous follicle-stimulating hormone-related increase in serum estradiol levels. The present article reviews the different protocols of ovarian hyperstimulation for cancer patients, candidates for fertility preservation.

Fertility preservation in Turner syndrome.

Premature ovarian insufficiency is a relatively rare condition that can appear early in life. In a non-negligible number of cases the ovarian dysfunction results from genetic diseases. Turner syndrome (TS), the most common sex chromosome abnormality in females, is associated with an inevitable premature exhaustion of the follicular stockpile. The possible or probable infertility is a major concern for TS patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The severely reduced follicle pool even during prepubertal life represents the major limit for fertility preservation and is the root of numerous questions regarding the competence of gametes or ovarian tissue crybanked. In addition, patients suffering from TS show higher than usual rates of spontaneous abortion, fetal anomaly, and maternal morbidity and mortality, which should be considered at the time of fertility preservation and before reutilization of the cryopreserved gametes. Apart from fulfillment of the desire of becoming genetic parents, TS patients may be potential candidates for egg donation, gestational surrogacy, and adoption. The present review discusses the different options for preserving female fertility in TS and the ethical questions raised by these approaches.

The past, present and future of fertility preservation in cancer patients.

Fertility preservation strategies have been developed for men and women whose fertility is compromised for medical reasons, especially in case of cancer therapy. At present, many reliable options for preserving fertility are available. However, a part of these fertility preservation methods, despite being promising, are still considered experimental. Nevertheless, there are still situations where no methods can be offered. Remarkable scientific progress is currently underway to improve available techniques and to develop new technologies to solve problems with current fertility strategies. These new options may drastically change reproductive options for young patients facing germ cell loss and hence sterility. Therefore, oncofertility counseling by a specialist is recommended for all young cancer patients having to undergo treatment that may reduce fertility potential.

In vitro maturation of oocytes: uncommon indications.

Retrieval of immature oocytes from unstimulated ovaries, followed by in vitro maturation (IVM) was initially proposed to avoid the risks and side effects of exogenous gonadotropin administration. Therefore, during the past decades, IVM was mainly offered to patients with polycystic ovary syndrome (PCOS) at high risk of ovarian hyperstimulation syndrome (OHSS). However, the development of fertility preservation has recently opened new perspectives in the field of IVM. The present review summarizes uncommon indications of IVM, which is a viable option to treat infertility in patients with ovarian resistance to FSH, but may also be considered to preserve fertility in leukemia as well as before ovarian transposition and endometrioma excision.

The cognitive implications of asymmetric color generalization in honeybees.

Generalization occurs when a conditioned response formed to one stimulus is also elicited by other stimuli which have not been used in the course of conditioning. Here, we studied color generalization in honeybees Apis mellifera trained to two rewarded colors, S1+ and S2+. After training, bees were tested with non-rewarded novel stimuli, which lay between the trained stimuli in a honeybee color space (Int) or outside the range defined by the trained stimuli (E1 and E2). We analyzed whether bees interpolated their choice to Int and/or extrapolated it to E1 and E2. We compared the performances of the group trained with S1+ and S2+ to those of control groups trained only with S1+ or S2+. Bees trained with S1+ and S2+ responded similarly and highly to all test stimuli. These results do not allow discerning between generalization models based on the presence of interpolation and/or extrapolation. Nevertheless, bee's performance was consistent with a linear summation of the two generalization gradients generated by S1+ and S2+, respectively. These gradients were asymmetric because control bees responded to the test stimuli as if these belonged to different similarity classes in spite of the fact that they had similar perceptual distances separating them. Stimuli treated as similar were located in the same half of the color spaces, whereas stimuli treated as different were located in opposite halves. Our results suggest that color categories could exist in honeybees and may underlie the performance of the control groups. Under this assumption, color categories would be also present in simpler nervous systems, and would not require factors such as language to be expressed.