An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism.

BACKGROUND: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. METHODS: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 µg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). RESULTS: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. CONCLUSIONS: Corifollitropin alfa 150 µg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01709331 .

Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.

A meta-analysis was conducted of individual patient data (n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18-36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35-42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5-1.5); vital pregnancy rate: -2.2% (95% CI: -5.3%-0.9%); ongoing pregnancy rate: -1.7% (95% CI: -4.7%-1.4%); and live birth rate: -2.0% (95% CI: -5.0%-1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82-1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81-2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH.

Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation.

AIM: The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. METHODS: Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 - 180 µg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. RESULTS: A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m(-2) ); 14% higher in women with a BMI of 18 kg m(-2) vs. 32 kg m(-2) (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. CONCLUSIONS: Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label.

Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.

BACKGROUND: This secondary analysis aimed to identify predictors of low (<6 oocytes retrieved) and high ovarian response (>18 oocytes retrieved) in IVF patients undergoing controlled ovarian stimulation with corifollitropin alfa in a gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: Statistical model building for high and low ovarian response was based on the 150 µg corifollitropin alfa treatment group of the Pursue trial in infertile women aged 35-42 years (n = 694). RESULTS: Multivariable logistic regression models were constructed in a stepwise fashion (P <0.05 for entry). 14.1 % of subjects were high ovarian responders and 23.2 % were low ovarian responders. The regression model for high ovarian response included four independent predictors: higher anti-Müllerian hormone (AMH) and antral follicle count (AFC) increased the risk, and higher follicle-stimulating hormone (FSH) levels and advancing age decreased the risk of high ovarian response. The regression model for low ovarian response also included four independent predictors: advancing age increased the risk, and higher AMH, higher AFC and longer menstrual cycle length decreased the risk of low ovarian response. CONCLUSIONS: AMH, AFC and age predicted both high and low ovarian responses, FSH predicted high ovarian response, and menstrual cycle length predicted low ovarian response in a corifollitropin alfa/GnRH antagonist protocol. TRIAL REGISTRATION NUMBER: NCT01144416 , Protocol P06029.

Cognitive Training With Head-Mounted Display Virtual Reality in Neurorehabilitation: Pilot Randomized Controlled Trial.

BACKGROUND: Neurological rehabilitation is technologically evolving rapidly, resulting in new treatments for patients. Stroke, one of the most prevalent conditions in neurorehabilitation, has been a particular focus in recent years. However, patients often need help with physical and cognitive constraints, whereby the cognitive domain in neurorehabilitation does not technologically exploit existing potential. Usually, cognitive rehabilitation is performed with pen and paper or on a computer, which leads to limitations in preparation for activities of daily living. Technologies such as virtual reality (VR) can bridge this gap. OBJECTIVE: This pilot study investigated the use of immersive VR in cognitive rehabilitation for patients undergoing inpatient neurorehabilitation. The goal was to determine the difference in rehabilitation effectiveness between a VR serious game that combines everyday activities with cognitive paradigms and conventional computerized cognitive training. We hypothesized the superiority of the VR serious game regarding cognitive abilities and patient-reported outcomes as well as transfer to daily life. METHODS: We recruited 42 patients with acute brain affection from a German neurorehabilitation clinic in inpatient care with a Mini Mental Status Test score >20 to participate in this randomized controlled trial. Participants were randomly assigned to 2 groups, with 1 receiving the experimental VR treatment (n=21). VR training consisted of daily life scenarios, for example, in a kitchen, focusing on treating executive functions such as planning and problem-solving. The control group (n=21) received conventional computerized cognitive training. Each participant received a minimum of 18 treatment sessions in their respective group. Patients were tested for cognitive status, subjective health, and quality of life before and after the intervention (Alters-Konzentrations-Test, Wechsler Memory Scale-Revised, Trail Making Test A and B, Tower of London-German version, Short Form 36, European Quality of Life 5 Dimensions visual analog scale, and Fragebogen zur Erfassung der Performance in VR). RESULTS: Repeated-measures ANOVA revealed several significant main effects in the cognitive tests: Tower of London-German version (P=.046), Trail Making Test A (P=.01), and Wechsler Memory Scale-Revised (P=.006). However, post hoc tests revealed that the VR group showed significant improvement in the planning, executive control, and problem-solving domains (P=.046, Bonferroni P=.02). In contrast, no significant improvement in the control group between t0 and t1 was detected (all P>.05). Furthermore, a nonsignificant trend was observed in visual speed in the VR group (P=.09, Bonferroni P=.02). CONCLUSIONS: The results of this pilot randomized controlled trial showed that immersive VR training in cognitive rehabilitation had greater effectiveness than the standard of care in treating patients experiencing stroke in some cognitive domains . These findings support the further use and study of VR training incorporating activities of daily living in other neurological disorders involving cognitive dysfunction. TRIAL REGISTRATION: Federal Registry of Clinical Trials of Germany (DRKS) DRKS00023605; https://drks.de/search/de/trial/DRKS00023605.

The estimated annual cost of uterine leiomyomata in the United States.

OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually. CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors.

Single umbilical artery: Does side matter?

INTRODUCTION: The aim of this study was to determine if laterality of an absent umbilical artery (AUA) is associated with specific sonographic findings, chromosomal defects or postpartum birth defects. MATERIALS AND METHODS: In this retrospective cohort study, ultrasound reports and medical records of patients who received an obstetric ultrasound at the University of Iowa Hospitals and Clinics with an identified laterality of the AUA from 1989 to 2007 (n = 405) were reviewed. Rates of sonographic abnormalities between fetuses with a right versus left AUA were compared using Fisher's exact test. Adjustments for confounding were made using logistic regression modeling. The significance level was set at 0.05. RESULTS: Right AUAs on ultrasound demonstrate higher unadjusted rates of ultrasound abnormalities with a higher percentage of fetuses with >1 additional abnormality (51.1 vs. 37.0%; p = 0.0043). The left AUA group had a significantly higher percentage of isolated AUA (63.0 vs. 48.8%; p = 0.004). In a multivariate analysis, a sonographic right AUA was significantly associated with gastrointestinal (GI) and genitourinary (GU) abnormalities. No other ultrasonographic and umbilical artery Doppler abnormalities, chromosomal defects or postpartum birth defects were significantly associated with a specific laterality of the AUA. DISCUSSION: Our study identified a significant association between a right AUA and concomitant fetal GI and GU abnormalities. Contrary to previous reports, we conclude that laterality of the AUA may prove to be an easily identified early marker of fetal abnormalities.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

CONTEXT: Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. OBJECTIVE: We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. METHODS: This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 µg if weight ≤ 60 kg, or 150 µg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. RESULTS: After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. CONCLUSION: Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles.

BACKGROUND: Various experiments suggest that ovarian follicular recruitment and growth may be increased by testosterone priming. Our aim was to determine the effects of exogenous testosterone supplementation in older women on ovarian folliculogenesis and steroidogenesis. METHODS: A prospective randomized double-blind placebo-controlled crossover study was carried out. Twelve regularly menstruating non-obese women aged 38-45 years received a 12-day course of transdermal testosterone (2.5 mg per patch) or placebo patch, followed by 7 days of gonadotrophin stimulation. After at least a 1 month washout period, subjects underwent the same protocol using the opposite treatment. The main outcomes were follicular development (ultrasound measures) and hormone levels. RESULTS: Following gonadotrophin stimulation, there were no differences in average number of follicles over 10 mm diameter in cycles pre-treated with testosterone versus placebo [2.10 (95% confidence interval (CI) 1.11, 3.22) versus 2.08 (95% CI 1.03, 3.14), P = 0.55]. No crossover, period (first or second test) or sequence (order of treatment) effects were noted. As expected, total and free testosterone levels were increased following testosterone treatment (312.7 +/- 122.4 versus 12.3 +/- 4.5 ng/dl and 45.5+/- 16.7 versus 1.4 +/- 0.5 ng/dl, respectively, P < 0.001) but no differences in free or total testosterone were noted by period. LH, FSH, estradiol and antral follicle counts before gonadotrophin stimulation were not altered by testosterone pretreatment or by period. CONCLUSIONS: Despite increased testosterone levels, a short course of androgens had no significant effect on the number of follicles over 10 mm during stimulation with FSH in women of late reproductive age.

Hypothalamic-Pituitary-Adrenal Axis Responses in Women with Endometriosis-Related Chronic Pelvic Pain.

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 µg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.

Efficacy and safety of frozen-thawed embryo transfer in women aged 35 to 42 years from the PURSUE randomized clinical trial.

OBJECTIVE: To examine the efficacy and safety of frozen-thawed embryo transfer (FTET) cycles with supernumerary embryos cryopreserved during a randomized clinical trial (PURSUE). DESIGN: Follow-up clinical study. SETTING: In vitro fertilization (IVF) centers. PATIENT(S): Infertile women 35 to 42 years of age. INTERVENTION(S): In PURSUE, women were randomized to a single injection of 150 µg of corifollitropin alfa (n = 694) or daily 300 IU of recombinant follicle-stimulating hormone (recombinant FSH; n = 696) for the first 7 days of controlled ovarian stimulation (COS) in a gonadotropin-releasing hormone (GnRH) antagonist protocol. MAIN OUTCOME MEASURE(S): Cumulative vital pregnancy rate per-patient by treatment group, cumulative live-birth rate per-patient by treatment group, and occurrence of adverse events in (pregnant) women and their fetuses/infants and the incidence of congenital malformations in the infants. RESULT(S): Of the 1,390 treated women in PURSUE, 307 were enrolled in the FTET study. In PURSUE or a subsequent FTET cycle, the cumulative vital pregnancy rate (per patient) was 31.1% (95% confidence interval [CI], 27.7%; 34.7%) with corifollitropin alfa versus 33.0% (95% CI: 29.6%; 36.7%) with recombinant FSH; treatment difference, -1.8% (95% CI, -6.5%; 3.0%), and the cumulative live-birth rate (per patient) was 28.2% (95% CI, 24.9%; 31.8%) with corifollitropin alfa versus 29.5% (95% CI, 26.1%; 33.0%) with recombinant FSH; treatment difference, -1.2% (95% CI, -5.7%; 3.4%). There were no clinically relevant differences in safety outcomes collected from pregnant women or their infants after transfer of cryopreserved embryos obtained by treatment with corifollitropin alfa or recombinant FSH. CONCLUSION(S): The cumulative vital pregnancy and live-birth rates (from fresh cycles and FTET) were similar in women treated with corifollitropin alfa and recombinant FSH. No new safety signals were detected in this follow-up FTET study. CLINICAL TRIAL REGISTRATION NUMBER: NCT01146418.

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

STUDY QUESTION: What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels? SUMMARY ANSWER: The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm. WHAT IS KNOWN ALREADY: In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. STUDY DESIGN, SIZE, DURATION: From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. MAIN RESULTS AND THE ROLE OF CHANCE: The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. WIDER IMPLICATIONS OF THE FINDINGS: For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878.

Changes in antimüllerian hormone levels in early pregnancy are associated with preterm birth.

OBJECTIVE: To determine the association of preterm birth with antimüllerian hormone (AMH) levels both in isolation and in combination with other markers of fetoplacental health commonly measured during integrated prenatal screening (IPS) for aneuploidy. DESIGN: Retrospective case-control study. SETTING: Not applicable. PATIENT(S): Pregnant women in Iowa who elected to undergo IPS and who subsequently delivered in Iowa, including women giving birth at <37 weeks' gestation and controls who delivered at ≥37 weeks' gestation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Probability of a preterm birth. RESULT(S): Second trimester AMH levels were not associated with preterm birth, either independently or after controlling for other markers of fetoplacental health. The AMH difference was not associated with preterm birth when modeled alone, but a statistically significant association was found after adjusting for maternal serum α-fetoprotein (MSAFP) and maternal weight change between the first and second trimesters. After stratifying the model by MSAFP level, most of the risk for preterm birth was identified in women with an MSAFP >1 multiple of the median and who had a stable or rising AMH level in early pregnancy. CONCLUSION(S): A lack of decline in the AMH level in early pregnancy can be used to identify women with a high probability for preterm birth, especially when MSAFP levels are >1 multiple of the median. Monitoring changes in the AMH level between the first and second trimesters of pregnancy may help identify women who would benefit from interventional therapies such as supplemental progesterone.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization.

OBJECTIVE: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN: Phase 3 randomized, double-blind, noninferiority trial. SETTING: Multicenter trial. PATIENT(S): A total of 1,390 women aged 35-42 years. INTERVENTION(S): A single injection of 150 µg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S): Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S): Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S): Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: NCT01144416.

Other nonstress influences can alter salivary α-amylase activity.

Clearly, more research is required to fully evaluate the impact of stress on both fertile and infertile women, and discovery of a biomarker that correlates well with psychosocial stress would be a great advantage to researchers. This article is a first step toward that goal, but it may be premature to assign these findings to stress alone.

Effect of vitrification and thawing on human oocyte ATP concentration.

Vitrification/thawing has a significant negative impact on oocyte ATP concentration. However, incubating oocytes up to 180 minutes after thawing allowed oocytes to regain some ATP level.

Proficiency in oocyte retrieval: how many procedures are necessary for training?

OBJECTIVE: To determine a minimum number of procedures required for proficiency in oocyte retrieval and to characterize skill acquisition. DESIGN: Retrospective analysis. SETTING: Reproductive endocrinology and infertility fellowship training program. SUBJECT(S): Fellows in training from 2005 to 2007 and 2008 to 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proficiency scores were calculated by dividing the number of oocytes retrieved by oocytes expected. The 2005 to 2007 trainees were grouped and proficiency scores calculated as an average during specific points in their training. The 2008 to 2010 trainees were compared individually to determine differences in individual skill acquisition. RESULT(S): A greater number of oocytes were retrieved than expected, 8.6 versus 7.6. A relatively lower proficiency score was noted during the first 10 trainee aspirations (proficiency score=1.1) compared with subsequent aspirations (proficiency score=1.25 for retrievals 11-20, proficiency score=1.21 for retrievals 21-30 and >31). When individual fellows' scores were calculated, the majority achieved proficiency by 20 aspirations, and all but one trainee achieved the mean staff proficiency score by 50 retrievals. CONCLUSION(S): Regardless of a trainee's initial proficiency in oocyte retrieval, there were no statistically significant differences in the learning curve between trainees. The majority of individual fellows in training demonstrate proficiency in follicular aspirations within 20 procedures; however, a minority may require 50 procedures to achieve the proficiency of an attending physician.

In vitro fertilization patients support a single blastocyst transfer policy.

OBJECTIVE: To determine whether patients support a mandatory single blastocyst transfer (mSBT) policy in IVF. DESIGN: Prospective survey study. SETTING: Academic hospital-based infertility center. PATIENT(S): Two hundred sixty-two female patients presenting for fresh or cryopreserved/thawed ET after IVF. INTERVENTION(S): Internet-based in-clinic survey after ET. Follow-up at-home survey after pregnancy test results. MAIN OUTCOME MEASURE(S): Patient support for an mSBT policy and attitudes regarding patient input into IVF treatment. Logistic regression analyses tested associations among main outcome measures, patient characteristics, and treatment results. RESULT(S): Ninety-four percent of patients endorsed support for our mSBT policy; 95% and 87% felt they had the right amount of input in their IVF treatment and number of embryos transferred, respectively, and these subjects were more likely to support the mSBT policy. Other factors associated with stronger support were concern for multiples, availability of extra cryopreserved embryos, and shorter duration of infertility. Receiving a single blastocyst during treatment did not change the level of support. A negative pregnancy outcome decreased support, however. CONCLUSION(S): Policies restricting the number of embryos transferred may find wide patient acceptance.

Five-years of a mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate without lowering pregnancy rates.

OBJECTIVE: To report the outcomes of a program policy instituted in 2004 mandating single-embryo transfer (mSET) for all women aged <38 years, with at least seven zygotes, no prior failed fresh cycle at our center, and at least one good-quality blastocyst. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): All women <38 years old undergoing a fresh cycle with autologous oocytes and all women undergoing a fresh cycle with donor oocytes from June 1, 1999, to May 31, 2004 (before mSET) and from June 1, 2004, to May 31, 2009 (after mSET). INTERVENTION(S): mSET policy implementation. MAIN OUTCOME MEASURE(S): Live-birth rate, multiple pregnancy rate, clinical volume, and outcomes of all mSET fresh IVF transfers were analyzed. RESULT(S): Clinical volume was unchanged between the two time groups. After implementation of mSET, live-birth rates improved from 51.1% to 55.9% and multiple-birth rates dropped from 34.8% to 17.5%. A total of 364 mSET fresh transfers were performed with a live-birth rate of 64.6% and a multiple-birth rate of 3.4%. CONCLUSION(S): A mandatory SET policy based on prognostic factors can be instituted with no drop in clinical volume and no negative effect on delivery rates. Multiple gestation rates can be dramatically lowered.