Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study.

STUDY QUESTION: What are the outcomes of French emergency IVF procedures involving embryo freezing for fertility preservation before gonadotoxic treatment? SUMMARY ANSWER: Pregnancy rates after emergency IVF, cryopreservation of embryos, storage, thawing and embryo transfer (embryo transfer), in the specific context of the preservation of female fertility, seem to be similar to those reported for infertile couples undergoing ART. STUDY DESIGN, SIZE, DURATION: A French retrospective multicentre cohort study initiated by the GRECOT network-the French Study Group for Ovarian and Testicular Cryopreservation. We sent an e-mail survey to the 97 French centres performing the assisted reproduction technique in 2011, asking whether the centre performed emergency IVF and requesting information about the patients' characteristics, indications, IVF cycles and laboratory and follow-up data. The response rate was 53.6% (52/97). PARTICIPANTS/MATERIALS, SETTING, METHODS: Fourteen French centres reported that they performed emergency IVF (56 cycles in total) before gonadotoxic treatment, between 1999 and July 2011, in 52 patients. MAIN RESULTS AND THE ROLE OF CHANCE: The patients had a mean age of 28.9 ± 4.3 years, and a median length of relationship of 3 years (1 month-15 years). Emergency IVF was indicated for haematological cancer (42%), brain tumour (23%), sarcoma (3.8%), mesothelioma (n = 1) and bowel cancer (n = 1). Gynaecological problems accounted for 17% of indications. In 7.7% of cases, emergency IVF was performed for autoimmune diseases. Among the 52 patients concerned, 28% (n = 14) had undergone previous courses of chemotherapy before beginning controlled ovarian stimulation (COS). The initiation of gonadotoxic treatment had to be delayed in 34% of the patients (n = 19). In total, 56 cycles were initiated. The mean duration of stimulation was 11.2 ± 2.5 days, with a mean peak estradiol concentration on the day on which ovulation was triggered of 1640 ± 1028 pg/ml. Three cycles were cancelled due to ovarian hyperstimulation syndrome (n = 1), poor response (n = 1) and treatment error (n = 1). A mean of 8.2 ± 4.8 oocytes were retrieved, with 6.1 ± 4.2 mature oocytes and 4.4 ± 3.3 pronuclear-stage embryos per cycle. The mean number of embryos frozen per cycle was 4.2 ± 3.1. During follow-up, three patients died from the consequences of their disease. For the 49 surviving patients, 22.5% of the couples concerned (n = 11) requested embryo replacement. A total of 33 embryos were thawed with a post-thawing survival rate of 76%. Embryo replacement was finally performed for 10 couples with a total of 25 embryos transferred, leading to one biochemical pregnancy, one miscarriage and three live births. Clinical pregnancy rate and live birth per couple who wanted a pregnancy after cancer were, respectively, 36% (95% CI = 10.9-69.2%) and 27% (95% CI = 6.0-61%). LIMITATIONS, REASONS FOR CAUTION: The overall response rate for clinics was 53.6%. Therefore, it is not only that patients may not have been included, but also that those that were included were biased towards the University sector with a response rate of 83% (25/30) for a small number of patients. WIDER IMPLICATIONS OF THE FINDINGS: According to literature, malignant disease is a risk factor for a poor response to COS. However, patients having emergency IVF before gonadotoxic treatment have a reasonable chance of pregnancy after embryo replacement. Embryo freezing is a valuable approach that should be included among the strategies used to preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Can anti-Müllerian hormone concentrations be used to determine gonadotrophin dose and treatment protocol for ovarian stimulation?

The ability to predict the response potential of women to ovarian stimulation may allow the development of individualized ovarian stimulation protocols. This tailored approach to ovarian stimulation could reduce the incidence of ovarian hyperstimulation syndrome in women predicted to have an excessive response to stimulation or could improve pregnancy outcomes in women classed as poor responders. Namely, variation of the type of gonadotrophin-releasing hormone (GnRH) analogue or the form and dosage of gonadotrophin used for stimulation could be adjusted according to an individual's response potential. The serum concentration of anti-Müllerian hormone (AMH) is established as a reliable marker of ovarian reserve, with decreasing concentrations correlated with reduced response potential. This review examines the current evidence evaluating individualized ovarian stimulation protocols using AMH concentration as a predictive marker of ovarian response. The rationale behind why specific treatment protocols based on individual response potential may be more suitable is also discussed. Based on current evidence, it appears that the use of AMH serum concentrations to predict ovarian response and optimize treatment strategies is a promising approach for improving pregnancy outcomes in women undergoing ovarian stimulation. However, prospective randomized controlled trials evaluating this approach are needed before any firm conclusions can be drawn.

Cardiovascular findings in women suffering from Turner syndrome requesting oocyte donation.

BACKGROUND: Through oocyte donation (OD), women with Turner syndrome (TS) may achieve motherhood. However, this population has a high prevalence of cardiac malformations and carry a risk for aortic dissection that is increased by pregnancy. Until recently, the necessity for a specialized cardiac evaluation before pregnancy was underestimated as was the need for follow-up through adulthood. The aim of this study was to evaluate the follow-up (mainly cardiovascular) of women with TS requesting OD. METHODS: Disease monitoring since diagnosis and prior cardiac evaluations conducted out of our centre were assessed in 25 women with TS who requested OD. New cardiac evaluations using echocardiography and magnetic resonance imaging were performed by our specialized cardiologist in 18 of these patients. RESULTS: We observed that the medical follow-up of women with TS was often deficient throughout adulthood. Most of the prior cardiac evaluations performed by cardiologists not accustomed to women with TS, either before (n = 8) or when starting OD (n = 12), were considered normal. However, when revaluated by a cardiologist who is familiar with TS, seven women were diagnosed with a bicuspid aortic valve and thus excluded from OD. In addition, when appropriate screening was conducted by our referent cardiologist before OD no cardiac complication was observed during pregnancy or delivery. CONCLUSIONS: Careful follow-up, including cardiac evaluation, should be recommended for women diagnosed with TS, before and after puberty. Moreover, assessment of cardiovascular parameters by a cardiologist familiar with TS should be routinely repeated before undertaking OD.

Infertility and endometriosis: a need for global management that optimizes the indications for surgery and ART.

Endometriosis causes pelvic pain and infertility. Infertility results from effects of endometriosis exerted in the pelvic cavity, in the ovaries and/or on the uterus. Medical treatment effective on pain and at preventing disease recurrence following surgery is of no use for improving the chances of conceiving naturally. Surgery however improves the chances of conceiving in the 12-18 months afterward. Endometriosis through extension of the disease to the ovaries may harm ovarian response to COS needed in ART. Surgery for endometrioma(s) may further reduce ovarian responses to COS in case of endometriosis. Remarkably however, reduced ovarian responses due to endometriosis are not necessarily associated with reduced oocyte quality and ART outcome. Pre-ART treatment with oral contraceptives (OC) improves ART outcome in case of ovarian endometriosis particularly, if endometriomas are present at the time of oocyte retrieval. This measure requires however that a proper OC-FSH/hMG interval is respected and that "LH" effects are provided during the ovarian stimulation, using either hMG or small doses of hCG. These latter precautions prevent the adverse outcome reported in case of pre-ART use of OC when ovarian stimulation is conducted using r-FSH exclusively.

Sperm nuclear vacuoles, as assessed by motile sperm organellar morphological examination, are mostly of acrosomal origin.

Microinjection of nuclear vacuole-free spermatozoa selected by motile sperm organellar morphological examination (MSOME) has been claimed to enhance assisted reproduction treatment outcome compared with intracytoplasmic sperm injection. However, the nature of these nuclear vacuoles is unclear, since their localization at the front of the sperm head suggests they might be of acrosomal origin. To study this hypothesis, acrosomal status was evaluated using Pisum sativum agglutinin staining on a smear, together with sperm organellar morphological examination using the same optics as for MSOME on 30 sperm samples from infertile patients, yielding >3200 spermatozoa. Vacuoles were present in 61% of spermatozoa when acrosomal material or intact acrosomes were observed, versus 29% when spermatozoa were acrosome reacted (P<0.0001). Induction of the acrosomal reaction by ionophore A23587 from 17.4% to 36.1% significantly increased the percentage of vacuole-free spermatozoa from 41.2% to 63.8% (P<0.001). These data suggest that most nuclear vacuoles are of acrosomal origin. Hence, the best spermatozoa selected by MSOME are mostly acrosome-reacted spermatozoa. As microinjection of spermatozoa with a persistent acrosome drastically hampers embryo development in animal models, this suggests that the improvement in pregnancy rates reported following intracytoplasmic injection of morphologically selected sperm might be due to the procedure allowing injection of acrosome-reacted spermatozoa.

[How does peritoneal fluid flow influence anatomical distribution of endometriotic lesions?]. / Etude de la distribution anatomique des lésions endométriosiques: un argument majeur en faveur de la participation de la théorie de la régurgitation dans la physiopathologie de l'endométriose.

Endometriosis is a common disease in gynecology. Many theories were proposed to explain the endometriosis pathogenesis. The distribution of the endometriosis lesions seems to be interesting in order to understand the endometriosis pathogenesis. This distribution is asymmetric. This asymmetric distribution of endometriosis is explained by the anatomy of the peritoneal cavity and by the intraperitoneal fluids. It strongly confirms the role of menstrual regurgitation and peritoneal fluid in the endometriosis genesis. The similar asymmetric distribution for all types of endometriosis (superficial lesions, ovarian endometriosis cyst, deep endometriosis) is an argument in favor of a unique origin for the different types of lesions.

[In-vitro fertilization: advantage and disadvantage of covering the costs of IVF/ICSI by the health insurance in Switzerland]. / Fécondation in vitro: intérêt et désavantage du remboursement par l'assurance maladie en Suisse.

In-vitro fertilization: advantage and disadvantage of covering the costs of IVF/CSI by the health insurance in Switzerland The reimbursement of certain infertility treatments (stimulation with/without insemination) whereas IVF/ICSI is not leads patients with an indication of IVF to prefer treatments of low efficacy. The costs of multiple pregnancies issued by reimbursed or non-reimbursed fertility treatments are paid by the society. There should be measures to reduce these costs and to take the money used today to pay the complications of infertility treatments to reimburse IVF. The efficacy of such a system (single embryo transfer) has been proven in Belgium since several years. The dangers of complete reimbursement (IVF treatment in cases without any chances of success, only because it is for free) can be avoided by an Efficacy and Safety Board.

[Quality of endometrial preparation]. / Qualité de la préparation endométriale.

The gold standard in endometrial preparation remains what has been established for oocyte donation receivers. This preparation requires E2 for 14 days and then P4 in isolation. Endometrial thickness can now be evaluated with three-dimensional ultrasound or with the VOCAL system, which can evaluate endometrial volume: however, the mean thickness of the endometrium only has a predictive value for pregnancy at 6 mm, on day 6 or on the day that hCG is triggered. Despite the technical progress made, Doppler ultrasound, which can evaluate endometrial and subendometrial blood flow, does not contribute valid responses as to uterine receptivity and the chances for pregnancy. However, the level of uterine contractions at embryo transfer is recognized as a major factor of implantation and, to obtain faster uterine quiescence, it is recommended to begin progesterone before the transfer. The need for prolonged progesterone maintenance in case of pregnancy continues to be debated.

[Breast cancer in young women: adjuvant therapy and fertility]. / Cancer du sein chez la jeune femme: traitements adjuvants et désir de grossesse.

Prognosis of breast cancer women has been dramatically improved by the adjuvant therapies. As the vast majority of patients are cured, the importance of long-term quality of life is growing. The question of the maternity is an essential concern for the young women who have to receive chemotherapy or several years of endocrine therapy. This problem is often underestimated and may lead to emotional distress, depression or anxiety. A regional multidisciplinary working group was set up in order to offer optimal information about fertility and cancer as to propose specific therapeutic reproduction options, when applicable. Specificity of the young patients' breast cancer, the treatment approaches and their impact on fertility are discussed in this paper.

[Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for oocyte donors]. / Valeurs comparées de la corifollitropine alpha et de la FSH quotidienne dans la stimulation ovarienne des donneuses d'ovocytes.

OBJECTIVES: To demonstrate that corifollitropin alfa is as effective as daily FSH in controlled ovarian stimulation of oocyte donors. METHODS: From January 2013 to October 2015, 77 cycles controlled ovarian stimulation, derived from a continuous cohort of 77 oocyte donors, were analyzed. After synchronization by oestroprogestatif or estrogens, ovarian stimulation was started by corifollitropin alfa (Group corifollitropin alfa) or by daily FSH (Group daily FSH). In both groups, a GnRH antagonist was used for the prevention of premature surge of luteinizing hormone (LH). The induction of ovulation was induced by a GnRH agonist. The duration of treatment, estradiol rate, numbers of mature oocytes, fertilization rate, clinical and ongoing pregnancies rates were evaluated in the two groups. RESULTS: There is no difference for the age, the markers of ovarian reserve and the duration of treatment. The average rate of estradiol on the eighth day of the stimulation is lower for the corifollitropin alfa (845±694.5 vs 1742±1177.3, P<0.001), there is no difference in the number of mature oocytes retrieved (14.4 vs 13.4, P=0.979), with a fertilization rate significantly higher in the corifollitropin alfa group (59.8% vs 49.3%, P<0.001). The rate of ongoing pregnancies is higher but without reaching significant difference in this same group (36.6% vs 26%, P=0.277). CONCLUSION: As compared to daily FSH, corifollitropin alfa, in oocyte donors offers, advantages in terms of ease of use with identical efficiency.

[Identification of the intercycle FSH signal in urine samples (uFSH)]. / Identification du signal FSH intercycle par la mesure de la FSH urinaire (FSHu).

OBJECTIVE: The intercycle FSH signal that initiates follicular recruitment and marks the functional onset of the menstrual cycle is of small amplitude and while it commonly occurs on cycle day 3, this often varies. Hence, its identification and measurement in serum (sFSH) requires serial daily samplings. We attempted to determine whether urine measurements of FSH (uFSH) could offer a non-invasive alternative, using a model where the intercycle FSH signal is controlled by timely use of exogenous E2. PATIENTS AND METHODS: Pilot prospective trial in 21 infertile women having received E2, from day 25 of the previous cycle until the 1st Friday after menses. Blood and first void urine samples were collected, starting on the last day of E2 (baseline) for assessing FSH and creatinin. A sonogram was performed for identification of maturing follicles (>12 mm). RESULTS: uFSH and uFSH/Cr showed good correlation with sFSH (R = 0.52 and 0.63, P < 0.0001 and P < 0.0001, respectively). In 15/21 patients who had an intercycle sFSH elevation, this was confirmed by uFSH elevation, both occurring within 2-4 days after stopping E2. In all these women, the sonogram showed evidence of impending ovulation. The amplitude of the uFSH signal was on average 3 times higher than its sFSH counterpart. In 6/21 women, no intercycle FSH elevation was detected and no ovulation occurred. DISCUSSION AND CONCLUSION: Our results show that the intercycle FSH signal can easily be identified and measured in urine. This novel approach permits more precise assessments of ovarian physiology than with blood measurements.

[Early pregnancy termination: what the generalist should know]. / L'interruption de grossesse précoce: ce que le praticien doit savoir.

Termination of pregnancy before 12 weeks after the last menstrual period is requested by an important number of women. We review the legal framework of abortion in Switzerland and the most used methods for medical abortion precising their contra-indications and most frequent complications. Very rare but fatal cases of infection following medical abortion (with mifepristone and misoprostol) were recently described. We present their clinical characteristics and discuss the related physiopathological process.

[Menopause: where are we three years beyond WHI?]. / Menopause: où en sommes-nous trois ans après la WHI?

The WHI triggered a great debate on Menopausal Hormonal Therapy. We now know that HT should not be used in cardio-vascular prevention. Many studies have yet been published regarding it's influence on breast cancers. Risks should be modulated in respect with the type of treatment and the targeted population. Only recently menopaused women or women suffering from invalidating menopausal symptoms should benefit from HT. When an HT is needed, the authors recommend the use of trans-cutaneous estrogens combined with natural oral progesterone. Every HT should be prescribed individually, according to the patient's aspirations and expectations.

[Reproductive endocrinology and infertility in the light of 20 years of IVF experience]. / Endocrinologie gynécologique et infertilité à la lumière de vingt ans de FIV.

In vitro fertilization (IVF)'s results have continuously improved over the past 20 years, making IVF part of routine services offered by most medical communities. The simplification of medical (ultrasound guided oocyte aspirations) and biological techniques (ready made media) contributed to the widespread development of IVF in the private sector, including in Switzerland. This challenges the needs of maintaining academic based IVF programs in the French speaking Switzerland. We believe however that IVF should remain part of academic gynecology because it also brings widespread collateral benefits that serve Gynecology notably, for teaching. Yet, the restricted size the French speaking Switzerland calls for creative approaches.

[When should we treat infertility and how should we determine the degree of urgency?]. / Quand traiter l'infertilité et comment déterminer le degré d'urgence?

The successes of assisted reproductive treatments (ART) have been amply documented. Yet, there is no clear consensus as to who are the couples who need ART and with which degree of urgency, short of course of those suffering from definitive tubal infertility or severe male factor. Determining the degree of medical urgency for deploying ART approaches is of true clinical concern. In case of occult forms of ovarian failure (not symptomatic short of infertility itself), delaying treatment may lead to definitive failure. Conversely, if infertility results from ovulatory disorders brought by stress, postponing ART for a few months may bring spontaneous pregnancies. The recent introduction of anti-mullerian hormone (AMH) testing is of significant help for assessing the degree of ovarian reserve.

Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.

OBJECTIVES: We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarction, or both. BACKGROUND: Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women; however, women with an intact uterus also take progestin to protect against uterine malignancies. The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown. METHODS: Eighteen postmenopausal women (mean +/- SD age 59+/-7 years) were given 17-beta-estradiol in single-blinded manner for four weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then continued, and the patients were randomized (double-blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. After another two weeks on estradiol alone, the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment. Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase. RESULTS: Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two patients (11%) were withdrawn while taking estradiol/MPA owing to unstable angina. CONCLUSIONS: Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.

Erectile dysfunction: to prescribe or not to prescribe?

Even with the help of modern pharmacology, treatment of erectile dysfunction often remains complex, and requires taking into account the social, psychological, and behavioral dimensions of the disorder. This brief report presents a case study highlighting this complexity.

[Use of aromatase inhibitors in infertile women]. / Utilisation des inhibiteurs de l'aromatase dans la prise en charge des femmes infertiles.

Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (D4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was too unspecific and these substances carried too many side effects for being used clinically. Today, however, 3rd generation AIs have become available that are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in post-menopausal women, either in advanced forms, or as part of adjuvant therapy. In women whose ovaries are active, a temporary inhibition of E2 production will activate gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. In infertile patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and in those who ovulate regularly but in whom multiple ovulation is sought for treating infertility or as part of IVF. Like CC, AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea. The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs' advantages over CC for induction of ovulation. Hence, we think that these drugs will play a key role for the induction of ovulation in the future.

[Menorrhagia and hemostatic abnormalities: diagnosis and treatment]. / Ménorragies et anomalies de l'hémostase: diagnostic et traitements.

Menorrhagias consisting of heavy menstrual bleeding are a common complaint, encountered in approximately 15% of women between the ages of 30 and 50. Diagnosis is difficult because women present different forms of excessive menses and no simple objective ways of measuring menstrual blood loss exist. A pictorial blood assessment chart was therefore validated for a better management of heavy menstrual bleeding. In half of the cases, no gynaecologic cause is found. Therefore, blood tests should be performed aiming at identifying coagulation disorders. We present here the results of our small series. Identification of coagulation disorders may allow specific treatments. These improve the quality of life and prevent unnecessary radical measures such as notably, hysterectomies.

Production of prolactin by cultures of cells from human decidua.

Human decidual tissue has been reported to secrete human PRL in vitro. Decidual scraped from fetal membranes delivered at term was treated with collagenase, and cultures of the dispersed cells were examined 7 days after plating. These cultures were fibroblastic in appearance and secreted insignificant amounts of PRL to the medium (less than 12 ng/ml). However, PRL-producing cells could be selected by taking advantage of the slowness of their attachment to the plastic dishes. Cultures of cells that did not attach during the first 48 h after cell dispersion produced, after attachment, about 100 micrograms PRL/mg DNA in 2 days. This rate is much higher than rates observed during batch incubations or superfusions of minced decidual preparations (approximately 0.2-0.3 micrograms PRL/mg DNA.day). PRL production rates declined after the seventh day of culture, probably as a consequence of overgrowth of cells that did not secrete PRL. Cultures enriched in PRL-secreting cells may be used to study the regulation of decidual production of PRL and other biochemical processes of the endometrium affected by decidualization.