Drug-free in-vitro activation of follicles and fresh tissue autotransplantation as a therapeutic option in patients with primary ovarian insufficiency.

RESEARCH QUESTION: Could in-vitro action of follicles and fresh tissue autotransplantation without tissue culture (drug-free IVA) be useful in patients with primary ovarian insufficiency (POI)? DESIGN: Prospective observational cohort study in a tertiary university hospital. Drug-Free IVA was carried out in 14 women with POI with a median age of 33 years (29-36 years), median length of amenorrhoea of 1.5 years (1-11 years), median FSH levels 69.2 mIU/ml (36.9-82.8 mIU/ml) and anti-Müllerian hormone of 0.02 ng/ml (0.01-0.1 ng/ml). The surgical procedure included laparoscopic removal of ovarian cortex, fragmentation of tissue and autografting. Human menopausal gonadotrophin (HMG) was started immediately after surgery. RESULTS: Follicle development was detected in seven out of the 14 patients, and five women achieved successful oocyte retrieval. In six women, HCG was administered in 10 cycles. Six embryo transfers were carried out in five women resulting in four pregnancies; a clinical pregnancy rate of four in seven oocyte retrievals and four in six embryo transfers. CONCLUSIONS: Drug-free IVA could be a useful therapeutic option for patients with POI, leading to successful IVF outcomes.

Ulipristal Acetate Improves Clinical Symptoms in Women with Adenomyosis and Uterine Myomas.

STUDY OBJECTIVE: To study the effects of ulipristal acetate (UPA) on adenomyosis-associated clinical symptoms. DESIGN: A retrospective, single-center observational study (Canadian Task Force classification II-2). SETTING: A university tertiary referral center. PATIENTS: Premenopausal women (163) with adenomyosis and symptomatic uterine myomas (41 patients, A + F group) versus a control group with only myomas (122 patients, F group) treated with the first course of UPA. INTERVENTIONS: This was a retrospective study to assess the effects of a 12-week course of UPA (5 mg/d). MEASUREMENTS AND MAIN RESULTS: Clinical symptoms including bleeding control, amenorrhea, pain outcomes, and self-perceived severity of the disease and quality of life. Amenorrhea was present in 90.4% of the A + F group compared with 77.6% in the F group (p = .0017). Optimal bleeding control was significantly higher in the adenomyosis group (pictorial blood loss assessment chart < 75) than in the F group (90.2% vs 73.8%, p = .028). At the end of the first UPA course, the self-reported visual analog scale scores in the A + F group were significantly higher than in the F group (p = .017), reflecting greater improvement in pain outcomes for women with adenomyosis. UPA treatment improved the quality of life in both study groups. Most of the women rated their global health status as "better" after the first UPA course than before the treatment (A + F group: 67.00% and F group: 80.50%, p = .223). CONCLUSION: Treatment with UPA led to a significant reduction in the clinical symptoms of adenomyosis (bleeding and pain) and achieved a high rate of amenorrhea in a cohort of women with concomitant uterine myomas. Despite the limitations of the study, our results showed that UPA might be a good alternative treatment for adenomyosis.

Contribution of Amniotic Fluid along Gestation to the Prediction of Perinatal Mortality in Women with Early Preterm Premature Rupture of Membranes.

INTRODUCTION: To evaluate the largest vertical pocket (LVP) of amniotic fluid as a time-dependent factor to predict perinatal mortality in women with early preterm premature rupture of membranes (EPPROM). MATERIAL AND METHODS: Observational cohort study of singleton pregnancies with EPPROM <24 weeks. Termination of pregnancy (TOP) was considered if the LVP was <2 cm at 7 days. The maternal and neonatal characteristics of ongoing pregnancies were recorded. Prediction of perinatal mortality was estimated based on the influence of the LVP as a time-dependent factor after adjustment for maternal age, prior invasive procedure, and gestational age at EPPROM. RESULTS: Of 104 women, 39 requested TOP. Neonatal survival to discharge was 40%, increasing to 74% if pregnancies achieved 24 weeks. LVP at admission <1 cm, latency to delivery, and gestational age at delivery were independent predictors of perinatal mortality. When evaluating the LVP at different time points of gestation, the highest perinatal mortality risk was established at 2 weeks (odds ratio 14.67, p < 0.001) after membrane rupture, being 5.75 (p = 0.05) the week after and 10.93 (p = 0.037) beyond 2 weeks of EPPROM. DISCUSSION: When LVP measurement, gestational age at EPPROM, maternal age, and prior invasive procedure were considered, we found that the worst prognosis related to perinatal mortality was at 2 weeks after EPPROM.

Definition of Failed Induction of Labor and Its Predictive Factors: Two Unsolved Issues of an Everyday Clinical Situation.

OBJECTIVE: The objectives of this review were to identify the predictive factors of induction of labor (IOL) failure or success as well as to highlight the current heterogeneity regarding the definition and diagnosis of failed IOL. MATERIALS AND METHODS: Only studies in which the main or secondary outcome was failed IOL, defined as not entering the active phase of labor after 24 h of prostaglandin administration ± 12 h of oxytocin infusion, were included in the review. The data collected were: study design, definition of failed IOL, induction method, IOL indications, failed IOL rate, cesarean section because of failed IOL and predictors of failed IOL. RESULTS: The database search detected 507 publications. The main reason for exclusion was that the primary or secondary outcomes were not the predetermined definition of failed IOL (not achieving active phase of labor). Finally, 7 studies were eligible. The main predictive factors identified in the review were cervical status, evaluated by the Bishop score or cervical length. DISCUSSION: Failed IOL should be defined as the inability to achieve the active phase of labor, considering that the definition of IOL is to enter the active phase of labor. A universal definition of failed IOL is an essential requisite to analyze and obtain solid results and conclusions on this issue. An important finding of this review is that only 7 of all the studies reviewed assessed achieving the active phase of labor as a primary or secondary IOL outcome. Another conclusion is that cervical status remains the most important predictor of IOL outcome, although the value of the parameters explored up to now is limited. To find or develop predictive tools to identify those women exposed to IOL who may not reach the active phase of labor is crucial to minimize the risks and costs associated with IOL failure while opening a great opportunity for investigation. Therefore, other predictive tools should be studied in order to improve IOL outcome in terms of health and economic burden.

Long-term outcome of ovarian function after drug-free in vitro activation (IVA) in primary ovarian insufficiency patient.

Drug-Free IVA has been recently introduced as a therapeutic option for patients with Primary Ovarian Insufficiency (POI). Despite the existing limited results, it can be considered as a promising option for these patients to achieve their own offspring. Here we report the case of a 35-year-old woman diagnosed with POI at 30 years of age. Drug-Free IVA was performed at age 33 and pregnancy was achieved by IVF 10 months after grafting. Unfortunately, she had a preterm delivery with neonatal death due to prematurity complications. After delivery, she recovered spontaneous ovarian function and one mature oocyte was retrieved 20 months after Drug-Free IVA. Following IVF, one embryo was transferred, and she is currently 33 weeks pregnant, suggesting that Drug-free IVA could lead to long-term ovarian function.

In Vitro Follicular Activation and Stem Cell Therapy as a Novel Treatment Strategies in Diminished Ovarian Reserve and Primary Ovarian Insufficiency.

Usually poor ovarian response (POR) to gonadotropins reflects a diminished ovarian reserve (DOR) that gives place to few recruitable follicles despite aggressive stimulation. The reduction in the quantity and quality of the oocytes with advanced age is physiological. However, some women experience DOR much earlier and become prematurely infertile, producing an accelerated follicular depletion towards primary ovarian insufficiency (POI). Up to now, egg donation has been commonly used to treat their infertility. In the last thirty years, specialists in assisted reproduction have focused their attention on the final stages of folliculogenesis, those that depend on the action of gonadotrophins. Nevertheless, recently novel aspects have been known to act in the initial phases, with activating and inhibiting elements. In vitro activation (IVA) combining the in vitro stimulation of the ovarian Akt signaling pathway in ovarian cortex fragments with a method named Hippo-signaling disruption. Later, a simplification of the technique designated Drug-Free IVA have shown encouraging results in patients with POI. Another innovative therapeutic option in these patients is the infusion of bone marrow-derived stem cells (BMDSC) in order to supply an adequate ovarian niche to maintain and/or promote follicular rescue in patients with impaired or aged ovarian reserves. In this review, for the first time, both therapeutic options are addressed together in a common clinical setting. The aim of this review is to analyze the physiological aspects on which these innovative techniques are based; the preliminary results obtained up to now; and the possible therapeutic role that they may have in the future with DOR and POI patients.

Comparison of GnRH agonist versus luteal estradiol GnRH antagonist protocol using transdermal testosterone in poor responders.

OBJECTIVE: Transdermal testosterone has been used in different doses and in different stimulation protocols in poor responders. The aim of the present study is to compare the luteal estradiol/GnRH antagonists protocol versus long GnRH agonists in poor responder patients according to the Bologna criteria, in which transdermal testosterone has been used prior to the stimulation with gonadotropins. METHODS: In this retrospective analysis, a total of 141 poor responder patients according to the Bologna criteria were recruited. All patients were treated with transdermal testosterone preceding ovarian stimulation with gonadotropins during 5 days. In 53 patients we used the conventional antagonist protocol (Group 1). In 88 patients (GrH pituitary suppression was achieved by leuprolide acetate according to the conventional long protocol (Group 2). We analyzed the ovarian stimulation parameters and IVF outcomes. RESULTS: Comparing groups 1 and 2, there were no significant differences between cancellation rates and number of oocytes retrieved. However the total gonadotropin dose used and the mean length of stimulation were significantly lower in group 1 when compared to group 2. There were no significant differences in pregnancy outcomes; however, there was a slight increase in the implantation rate in group 1 vis-a-vis group 2, although statistical significance was not achieved. CONCLUSION: TT in poor responder patients can be effective both with the conventional agonist's long protocol and with the conventional antagonist's protocol. However, short regimes with previous estradiol antagonists in the luteal phase facilitate ovarian stimulation by shortening the days of treatment and the consumption of gonadotropins.

Transmyometrial embryo transfer as a useful method to overcome difficult embryo transfers - a single-center retrospective study.

OBJECTIVE: Pregnancy after an embryo transfer depends largely on embryo quality, endometrial receptivity, and the technique used in the embryo transfer. Embryo transfers have been reported as inevitably traumatic and difficult for 5-7% of patients in assisted reproduction treatment. In these cases, transmyometrial embryo transfer should be considered as a suitable method to overcome difficult embryo transfers. The aim of this study was to report our experience with this technique and analyze its causes, results and complications. METHODS: Since 1993, 39 women (40 cycles of assisted reproductive technology treatment) were submitted to transmyometrial embryo transfers in our center. The procedures were carried out as described by the Towako group. RESULTS: The enrolled female patients had a mean age of 34 years and a mean baseline FSH level of 6.89 IU/mL. The median number of retrieved oocytes was 7.50 and a mean of 2.63 embryos were transferred. Implantation rate was 9.5%. With respect to clinical results, pregnancy and miscarriage rates were 25% and 30%, respectively. Since there were two twin pregnancies, the live birth rate was 22.5% (9/40). No major complications were reported. CONCLUSION: Transmyometrial embryo transfer can and should be an option in cases of difficult/impossible transcervical embryo transfer.

Age, independent from ovarian reserve status, is the main prognostic factor in natural cycle in vitro fertilization.

OBJECTIVE: To analyze natural cycle IVF (NC-IVF) results according to patient age, ovarian reserve status following the Bologna criteria, cause of infertility, and modification of the cycle with the use of GnRH antagonist. DESIGN: Retrospective cohort study. SETTING: Tertiary-care university hospital. PATIENT(S): Nine hundred forty-seven natural cycles carried out in 320 patients. INTERVENTION(S): Analysis of 947 NC-IVF outcomes performed in one single center between January 2010 and December 2014. MAIN OUTCOME MEASURE(S): Pregnancy rates per cycle started, per ET, and per patient, as well as ongoing pregnancy rate at a minimum of 12 weeks of gestation. RESULT(S): Among the three age groups analyzed (≤35 years, 36-39 years, and ≥40 years), pregnancy rates per cycle were significantly lower in the older group of patients (11.4% vs. 11.6% vs. 5.9%). In addition, miscarriage rate (7.7% vs. 34.4% vs. 50%) and ongoing pregnancy rate (10.6% vs. 7.6%vs. 3.0%) were negatively affected by patient age. However, no differences were observed according to patient ovarian reserve status, cause of infertility, or modification of the cycle with GnRH antagonist. The multivariate logistic regression confirmed that patient age was the only variable that could predict pregnancy in NC-IVF cycles (odds ratio, 0.93; 95% confidence interval, 0.88-0.98). CONCLUSION(S): NC-IVF is a feasible and "patient-friendly" option to be offered to young patients, independent of their ovarian reserve status.