Priming with a gonadotropin-releasing hormone agonist before immature oocyte retrieval may improve maturity of oocytes and outcome in in vitro maturation (IVM) cycle: a case report.

BACKGROUND: The concept of using a gonadotropin-releasing hormone agonist (GnRH-a) instead of human chorionic gonadotropin for triggering ovulation in patients treated with an antagonist protocol for in vitro fertilization (IVF) has become a routine clinical practice. It may promote oocyte nuclear maturation, resumption of meiosis and cumulus expansion. It seems that this attempt could be beneficial in an in vitro maturation (IVM) oocyte cycle performed for polycystic ovarian syndrome as well as for other indications such as urgent fertility preservation in patients with malignancies or unusual indications. CASE PRESENTATION: We present the case of a Caucasian patient who needed fertility preservation when routine natural IVF treatment did not yield oocyte retrieval, followed by three IVM cycles, priming ovulation with a GnRH-a. In total, 12 oocytes were obtained, all matured 4.5 hours after incubation in maturation media. The fertilization rate after intracytoplasmic sperm injection was 83%. Six good-quality embryos were vitrified. CONCLUSIONS: It seems that triggering with a GnRH-a in selected cases may replace human chorionic gonadotropin in IVM of oocytes and could be highly beneficial in terms of obtaining high-grade embryos and possible pregnancy.

Late follicular progesterone to estradiol ratio is not influenced by protocols or gonadotropins used.

OBJECTIVE: Increased progesterone level during follicular phase seemed to be associated with decreased pregnancy rate. STUDY DESIGN AND METHODS: A prospective cohort study, 1.1.2012 - 31.8.13. The Progesterone (P) and Progesterone/Estrogen (P/E2) level on ovulation induction day were compared between the protocols and the different gonadotropins used. Roc analysis was calculated to determine the cutoff of P/E2 to predict delivery rates. P/E2 ratio was calculated as PX1000/e2 level. MAIN RESULTS: One hundred thirty-nine patients were enrolled to the study. No difference in the P level at hCG stimulation day between different protocols, however, E2 and P/E2 ratio were significantly lower in the long protocol compare with antagonist protocol 1757.7 ± 923.2 vs. 1342.9 ± 1223; P = 0.003 and 0.48 ± 0.31 vs. 0.83 ± 0.87; P = 0.038). The endometrium was significantly thicker in the long group compare with short and antagonist. Significantly more top-quality embryos (TOP) were achieved in the antagonist group. Comparable results between the types of gonadotropins used in regards with cycle characteristics and pregnancy and delivery rates. The P/E2 ratio which can predict live birth rate was found to be 0.45, AUC = 0.632, p = 0.02 and 95 % CI 0.525-0.738 and a significantly higher pregnancy and delivery rates at a P/E2 bellow 0.45. CONCLUSION: Endometrial receptivity is determined by the complex interactions of E2 and P.

IVM results are comparable and may have advantages over standard IVF.

Retrieval of immature oocytes from unstimulated ovaries, followed by in vitro maturation (IVM) was originally proposed in order to avoid side effects of gonadotropin administration. The target is to eliminate or significantly reduce the risk of ovarian hyperstimulation syndrome (OHSS) in patients with polycystic ovary syndrome (PCOS), drug cost and burden on patients. This technology was also suggested in treatment of normo-ovulatory women, fertility preservation or infrequent conditions such as failure of oocytes to mature or repeated development of poor quality embryos. In this study we intended to examine the possibility that IVM results may be comparable to standard IVF. A PubMed database search from 1999-2013 was carried out for publications concerning the indications of IVM and study the possibility that IVM results may be comparable to standard IVF. In vitro maturation of the oocytes procedures obtained up to 35% clinical pregnancy rate in young women, comparable with in vitro fertilization (IVF) in many programs. The obstetric and perinatal outcomes of IVM cycles are comparable with IVF/ICSI cycles. In conclusion IVM may gradually replace IVF in certain cases, as the technique continues to develop and pregnancy rates continue to increase, being a promising and simple alternative approach to standard IVF in various indications.

In-vitro maturation of oocytes vs in-vitro fertilization with a gonadotropin-releasing hormone antagonist for women with polycystic ovarian syndrome: can superiority be defined?

OBJECTIVE: Patients with polycystic ovarian syndrome (PCOS) are at increased risk of ovarian hyperstimulation syndrome (OHSS) in controlled ovarian hyperstimulation cycles. Interventions to reduce the risk of OHSS in these patients include in-vitro fertilization (IVF) with a gonadotropin-releasing hormone (GnRH) antagonist, and retrieval of immature oocytes followed by in-vitro maturation (IVM). The aim of this study was to compare the outcomes of IVM and IVF-GnRH antagonist protocols in women with PCOS undergoing assisted reproductive technology. STUDY DESIGN: Retrospective cohort study. Records of women with PCOS who underwent IVM or IVF-GnRH antagonist protocols between 2010 and 2011 were reviewed. In total, there were 61 IVM cycles and 53 IVF-GnRH antagonist cycles. The treatment protocols were compared in terms of the number of oocytes retrieved, dose of gonadotropin administrated, fertilization rates, quality of embryos, pregnancy, and delivery and abortion rates. RESULTS: The number (mean±standard deviation) of mature oocytes did not differ significantly between the two groups (7.11±5.7 vs 8.16±5.07 for the GnRH antagonist group and the IVM group, respectively; p=0.38). The average dose of gonadotropin (1938 IU±838 IU/cycle vs 118±199 IU/cycle; p<0.001), fertilization rate (77% vs 60%; p<0.001) and high-quality embryo rate (58.8% vs 48.3; p<0.001) were significantly higher in the GnRH antagonist group compared with the IVM group. Pregnancy rates (40% vs 25%; p=0.08), livebirth rates per pregnancy (71% vs 53%; p=0.265) and abortion rates (10% vs 27%; p=0.17) were comparable. CONCLUSIONS: The IVM protocol can be an alternative for infertile women with PCOS who wish to prevent the potential adverse effects of gonadotropin treatment. Prospective studies are needed to compare the outcomes of these two treatment protocols.

Congenital malformations in infants conceived following assisted reproductive technology in comparison with spontaneously conceived infants.

OBJECTIVE: To evaluate the risk for congenital malformations diagnosed at birth following assisted reproductive technology (ART) treatments compared with live births conceived spontaneously. METHODS: A retrospective cohort study including 9042 live births following ART and 213 288 spontaneously conceived (SC) live births during the period 1997-2004.The cohort was linked to the national live birth registry to determine the outcome of the pregnancies including congenital malformations. RESULTS: An increased adjusted risk for all congenital malformations was observed in ART compared with SC infants [2.4% versus 1.9%; ORadj = 1.45; 95% CI: 1.26, 1.68]. The increased risk was observed in singleton births [2.4% versus 1.8%; ORadj = 1.41; 95% CI: 1.14, 1.71] but not in the ART conceived multiple births [2.5% versus 2.6%.; ORadj = 1.15; 95% CI: 0.90, 1.46]. Significantly increased adjusted risks for nervous, circulatory, digestive and genital system malformations were evident in the ART singleton group compared to SC infants. In addition, increased risks were also observed in separate comparisons of IVF births versus SC [ORadj = 1.28; 95% CI: 1.00, 1.63] and ICSI births versus SC [ORadj = 1.56; 95% CI: 1.31, 1.84]. Data regarding pregnancy termination or congenital malformation diagnosed later in life were not included. CONCLUSION: Infants born following ART were at significantly increased risk for congenital malformations compared to live birth conceived spontaneously.

Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS.

OBJECTIVE: To assess the efficacy and tolerability of the nondopaminergic agent XP13512/GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS). METHODS: Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 pm with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression-Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters. RESULTS: A total of 222 patients were randomized (XP13512 = 114, placebo = 108) and 192 patients (XP13512 = 100, placebo = 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (-13.2) compared with placebo (-8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of -4.0 (95% confidence interval [CI], -6.2 to -1.9; p = 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p < 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted. CONCLUSIONS: XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS.

How to improve IVF-ICSI outcome by sperm selection.

In previous studies, a new IVF method of intracytoplasmic morphologically selected sperm injection (IMSI) was introduced, based on motile sperm organellar morphology examination (MSOME). It was concluded that microinjection of morphologically selected sperm cells with strictly normal nucleus, defined by MSOME, improves IVF-ICSI outcome. The aim of the present study was to confirm this conclusion in new, enlarged study groups. Comparison between 80 couples, who underwent an IVF-IMSI trial, with matched couples, who underwent a standard IVF-ICSI procedure, confirmed that pregnancy rate following IVF-IMSI was significantly higher, and abortion rate significantly lower than in the routine IVF-ICSI (60.0 versus 25.0%, and 14 versus 40% respectively, P

A prospective, randomized controlled trial comparing the efficacy of recombinant follicle-stimulating hormone in three different in vitro fertilization protocols.

OBJECTIVE: To compare the following IVF protocols: a short protocol and long protocols starting on day 2 or day 21. All protocols used recombinant FSH (rFSH) for ovarian stimulation. DESIGN: Prospective, randomized study. SETTING: An assisted reproduction unit at a university center. PATIENT(S): Patients undergoing IVF (n = 150) were treated according to one of the three treatment protocols allocated by a random method. INTERVENTION(S): All patients used buserelin acetate and rFSH. Patients began the long protocol on day 2 (group 1) or day 21 (group 2) of the cycle. Patients in group 3 began the short protocol on day 2 of the cycle. MAIN OUTCOME MEASURE(S): Ovarian response, implantation rates, and pregnancy rates (PRs). RESULT(S): Patients treated with the short protocol (group 3) were stimulated in a shorter time, required less rFSH, and achieved higher E(2) levels. The numbers of follicles, oocytes, and embryos were similar in all three groups. The implantation rates were similar in groups 1 and 2 (11.8% and 13.3%, respectively), and both were higher than in group 3 (4.1%). Clinical PRs per oocytes retrieved were 19.6%, 18.6%, and 8.3% in groups 1, 2, and 3, respectively. CONCLUSION(S): The implantation rate was significantly higher with the long protocols than with the short protocol, with a tendency for a higher PR as well.

Effect of salpingectomy on ovarian response to superovulation in an in vitro fertilization-embryo transfer program.

OBJECTIVE: To investigate the effect of salpingectomy on the response of each ovary in patients undergoing an IVF-ET treatment cycle and to compare the results with those of patients who had not had surgery and were undergoing IVF-ET during the same period. DESIGN: A prospective study. SETTING: Tertiary referral academic IVF unit. PATIENT(S): Twenty-nine ET cycles were evaluated in 29 patients who previously had undergone unilateral salpingectomy because of ectopic pregnancy (study group). Seventy-three patients with unexplained or male factor infertility served as controls. INTERVENTION(S): Ovulation induction and IVF-ET. MAIN OUTCOME MEASURE(S): In the study group, mean ovarian volume, number of follicles, and number of oocytes recovered from each ovary were assessed and compared. The overall results, cycle characteristics, and pregnancy rates of the two groups were compared. RESULT(S): Among the patients who had undergone salpingectomy, significantly fewer follicles developed and consequently fewer oocytes were retrieved from the ovary on the operated side (4.4 versus 8.2 follicles and 3.8 versus 6.0 oocytes). There were no differences in the total numbers of follicles and oocytes recovered from both ovaries, the cycle characteristics, or the pregnancy rates between study and control groups. CONCLUSION(S): Salpingectomy has no detrimental effect on the total ovarian performance during IVF-ET treatment or on the outcome of IVF-ET. However, the ipsilateral ovary could be adversely affected. This could be detrimental in selected patients undergoing IVF-ET, in whom the second ovary already is compromised or missing.

Significance of sporadic deceleration during antepartum testing in term pregnancies.

We have investigated the significance of single sporadic deceleration during reactive nonstress testing in normal pregnancies at term. A prospective study was performed during a 1-year period including 4742 nonstress tests performed between the 38th and 42nd weeks of pregnancy in patients referred to our department for antepartum testing and without any complication or pathology. Nonstress test (NST) was carried out with the patient lying on her left side, and was defined as reactive if at least two accelerations of 15 beats/min (bpm) or more lasting 15 sec were observed in a 20-min period. Sporadic deceleration was defined as a decrease in the fetal heart rate to less than 90 bpm or a decrease of 40 bpm below the baseline, lasting at least 2 min. The sporadic deceleration was considered as single when only one appeared in the first 20 min of monitoring and repeated when observed again once in at least one subsequent monitoring. Thirty-four cases of single sporadic deceleration were observed among women with reactive NST. In 14 cases there were repeated sporadic decelerations. The patients were divided into two groups according to the presence or absence of repeated decelerations. Outcomes of patients with repeated sporadic decelerations were compared with a group of 34 patients where sporadic decelerations were not observed during the antepartum testing. A significantly higher percentage of pathological fetal heart rate traces during labor were observed in the group of repeated decelerations. In conclusion the presence of repeated sporadic decelerations during a reactive NST suggests that the cause of cord compromise is persistent and recurrent cord compression is possible. Therefore, in these cases an increased fetal risk could be expected.

The behavior of follicle cysts formed after long-acting gonadotropin-releasing hormone analog administration in patients with polycystic ovarian syndrome.

This study was conducted to examine the effect of ovarian cysts that develop after administration of a gonadotropin-releasing hormone (GnRH) analog during an ovulation induction program for patients with polycystic ovarian syndrome. Twenty-eight women received Decapeptyl Continuous Release for 70 cycles starting on day 3 of the menstrual cycle, after exclusion of any ovarian pathology by transvaginal ultrasonography. Fifteen days later ultrasonography was again performed and serum estradiol estimated. Cystic structures > or = 20 mm in the ovaries were defined as follicle cysts. In three cycles follicle cysts developed and low estradiol levels were measured (Group 1). In another six cycles cysts developed after GnRH analog, and elevated estradiol levels were found (Group 2). In the latter, estradiol decreased 3 to 7 days later, with cyst regression in three cases. Ovulation induction with human menopausal gonadotropin (hMG) was initiated only if the estradiol level was < or = 20 pg/ml, otherwise induction was postponed until estradiol decreased, disregarding the presence of cysts. When 2 to 3 follicles were > or = 18 mm, and generally when estradiol levels were < 1500 pg/ml, human chorionic gonadotropin was administered. All the cycles were ovulatory and two women from Group 2 conceived. The development of follicle cysts with low serum estradiol levels after GnRH analog administration represents a benign condition and is not a contraindication for hMG stimulation. In cases with elevated estradiol levels, ovulation induction can be postponed until the estradiol has decreased. Our study revealed good ovulatory and pregnancy rates as a result.

A follicular scoring system for monitoring ovulation induction in polycystic ovary syndrome patients based solely on ultrasonographic estimation of follicular development.

OBJECTIVE: To assess the predictive value of a follicular scoring system for monitoring ovulation induction in polycystic ovary syndrome (PCOS) patients, solely with ultrasound (US). DESIGN: Ultrasound measurements were performed on alternate days to define a serial follicular score for monitoring ovulation induction with hMG alone, as well as GnRH analogue and hMG, in comparison with E2 concentration obtained on the same day. SETTING: Outpatient Infertility Clinic, Department of Obstetrics and Gynecology. PATIENTS: Thirty-four consecutive PCOS patients treated for 63 cycles. MAIN OUTCOME MEASURE: The follicular score was established considering the summation of points obtained after measuring the mean diameter of each follicle > 5 mm, as follows: 5 to 8 mm = 1 point, 9 to 12 mm = 1.5 points, 13 to 16 mm = 2 points, > or = 17 mm = 3 points. RESULTS: Follicular score correlated positively with E2 concentrations. A score of > or = 30 points was associated with E2 levels of concentration that reached > 1,500 pg/mL (conversion factor to SI unit, 3.671) and could predict ovarian hyperstimulation. A lower follicular score allowed hCG administration. CONCLUSIONS: A follicular scoring system may be a safe, simple, and highly efficient method to replace serial E2 measurements in monitoring ovulation induction. Moreover, ovarian hyperstimulation may be predicted.

[Peak follicular estradiol (E2) levels and midluteal progesterone/E2 ratios in ongoing pregnancies and nonconception cycles after ovulation induced with gonadotropins].

We assessed the predictive value of peak follicular estradiol (E2) levels and progesterone/E2 ratios at the time of implantation (midluteal phase) in cycles resulting in pregnancies and in nonconception cycles after ovulation induced by hMG. hMG, administered to 31 consecutive patients with ovulatory dysfunction, resulted in 13 conception and 27 nonconception cycles. It was started on day 5 of the cycle and continued until at least 1 follicle was > 18 mm and E2 levels exceeded 300 pg/ml, when HCG, 100,000 IU, was administered. Baseline hormonal profile, peak follicular E2, serum E2, progesterone levels 7 days after hCG administration, and progesterone/E2 ratios were compared between ongoing pregnancies and during nonconception cycles. There was a significant difference in peak follicular E2 levels between ongoing pregnancies and nonconception cycles (means +/- SD: 1453 +/- 580 to 1176 +/- 275, pg/ml, p < 0.05). The length of follicular phase and the number of hMG ampules administered were similar in both groups. There was no difference in midluteal progesterone/E2 ratios (131 +/- 16.9 vs 124 +/- 27.5). E2 levels the day of hCG administration were higher in cycles leading to pregnancies. We conclude that mean midluteal progesterone/E2 ratios cannot be used to predict the outcome of cycles after ovulation induction with hMG.

Outcome of pregnancies associated with marked gestational thrombocytopenia.

The purpose of this prospective study was to investigate the outcome of pregnancies associated with marked gestational thrombocytopenias (< 100,000/mm3) including postpartum resolution and neonatal influence. Over a period of 18 months, 20 cases of thrombocytopenia were observed; of them 19 were diagnosed as gestational thrombocytopenia with platelet values of < 100,000/mm3. Fifteen women returned to a normal platelet count within two weeks after delivery and four within four weeks. No cases of thrombocytopenia were found among the infants and no cases of coagulation disturbance were observed in the mothers at delivery or in the postpartum period. The findings of the present study indicate that in cases of gestational thrombocytopenia, apart from a careful maternal and fetal surveillance, no intervention is necessary during pregnancy or delivery if there is no obstetrical indication.

Five missense mutations at the adenosine deaminase locus (ADA) detected by altered restriction fragments and their frequency in ADA--patients with severe combined immunodeficiency (ADA-SCID).

Severe combined immunodeficiency (SCID) is a heterogeneous syndrome, due to X-linked and autosomal recessive defects. A significant proportion of the autosomal recessive forms of SCID are due to mutations at the adenosine deaminase (ADA) locus. Nine different mutations at the ADA locus, including 7 missense point mutations, have been reported in children with ADA-SCID. We could detect 5 of the 7 missense mutations associated with ADA-SCID by alterations in restriction fragments utilizing standard restriction digestion of genomic DNA and hybridization of radiolabelled ADA genomic probes to Southern transfers. We additionally developed more rapid nonradioactive methods employing digestion of genomic DNA amplified by PCR that also detected all 5 mutations. Using these methods, we have examined a sample of 45 ADA-SCID chromosomes and report that these 5 missense mutations account for one third of the ADA--chromosomes studied, with 2 mutations being relatively common.

Hot spot mutations in adenosine deaminase deficiency.

We have previously characterized mutant adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4) enzymes in seven children with partial ADA deficiency. Six children shared common origins, suggesting a common progenitor. However, we found evidence for multiple phenotypically different mutant enzymes. We hypothesized that many of the mutations would be at CpG dinucleotides, hot spots at which spontaneous deamination of 5-methylcytosine results in C to T or G to A transitions. Digestion of DNA from these children with Msp I and Taq I, enzymes recognizing CpG dinucleotides, identified three different mutations, each correlating with expression of a different mutant enzyme. Sequencing of cDNA clones and genomic DNA amplified by polymerase chain reaction confirmed the presence of C to T or G to A transitions at CpG dinucleotides (C226 to T, G446 to A, and C821 to T, resulting in Arg76 to Trp, Arg149 to Gln, and Pro274 to Leu). A "null" mutation, also found in two ADA-deficient severe combined immunodeficient children, was serendipitously detected as gain of a site for Msp I. Simultaneous loss of a site for Bal I defined the precise base substitution (T320 to C, Leu107 to Pro), confirmed by sequence analysis. To determine the true frequency of hot spot mutation in these children, consecutively ascertained through a newborn screening program, we sequenced cDNA from the remaining alleles. Two others were hot spot mutations (C631 to T and G643 to A, resulting in Arg211 to Cys and Ala215 to Thr), each again resulting in expression of a phenotypically different mutant enzyme. Only one additional mutation (previously identified by us) is not in a hot spot. These seven mutations account for all 14 chromosomes in these children. There is thus a very high frequency of hot spot mutations in partial ADA deficiency. Most of these children carry two different mutant alleles. We were able to correlate genotype and phenotype and to dissect the activity of individual mutant alleles.

Smoking out the oestrogens.

PIP: A tentative yet comprehensive review of the effects of smoking on reproductive capacity includes conception, sperm morphology, teratogeny and intrauterine growth retardation, cancer, timing of menopause, estrogen secretion, in vitro fertilization and estrogen metabolism. Smokers are estimated to take 3.4 times as long as non-smokers to conceive, and are reported to be less fertile. Spermatozoa are both abnormal morphologically and genetically compromised, in proportion to dose. Smokers have greater viremia in mumps and can get mumps orchitis. Smoking is said to cause impotence. Smoking increases risk of spontaneous abortion, intrauterine growth retardation and congenital abnormalities, in proportion to dose, starting with sidestream smoke. Smoke is directly toxic to the ova, and indirectly deleterious because it decreases estrogen secretion. Women smokers tend to the thinner, with lower estrogen levels, a factor in their lower success rates with in vitro fertilization. Smoking may speed up metabolic degradation of estrogen via the 2-hydroxylation pathway as well. Finally, smokers have earlier menopause, with accompanying osteoporosis and fractures.^ieng

A scoring system for induction of labor using prostaglandin E2 vaginal tablets.

A randomized controlled trial was carried out in order to establish the efficacy of a scoring system for calculating the dose of vaginal prostaglandin E2 tablets for the induction of labor. One hundred ten women were included in the study. The patients received a dose of prostaglandin E2 calculated according to a scoring system based on the Bishop's score, or the standard dose of 3 mg repeated 6 h later if labor did not start. The percentage of inductions achieved was the same with both regimens (92.7%). The mean total dose used in the scoring system-group (2.7 mg) was significantly lower than that used in the 3-mg group (3.5 mg, P less than 0.025). Thirty-seven of 55 women receiving the scoring dose delivered with amounts of 2.5 mg prostaglandin E2 or less. Three cases of uterine hyperstimulation were observed in the 3-mg group whereas no cases were observed in the scoring group. The scoring system is proposed as a method for calculating the dose of vaginal prostaglandin E2 for induction of labor and minimizing the risk of overdosage.