Conventional ICSI vs. physiological selection of spermatozoa for ICSI (picsi) in sibling oocytes.

BACKGROUND: Physiological selection of spermatozoa for ICSI (PICSI) is a sperm selection method based on sperm binding to hyaluronic acid. Previous studies on the effect of hyaluronic acid binding assays on fertilization and embryo quality have shown inconsistent results. Previous sibling oocyte studies have not found a significant improvement in fertilization or embryo development with hyaluronic acid binding assays. OBJECTIVE: To compare fertilization and embryo development between standard intracytoplasmic sperm injection (ICSI) and PICSI in sibling oocytes. MATERIALS AND METHODS: This is a retrospective analysis of all in vitro fertilization (IVF) cycles between January 2017 and April 2020 in which sibling oocytes were randomly fertilized by both ICSI and PICSI. Fertilization rate and the rate of embryos eligible for transfer were compared. RESULTS: Forty-five IVF cycles, in which 257 oocytes were fertilized with PICSI and 294 with standard ICSI, were compared. Most of the patients included in the study had previous failures of fertilization, poor embryonic development, implantation failure, or miscarriage. All but two of the patients had at least one previous unsuccessful IVF cycle. Both fertilization rates (71% vs. 83%) and transfer eligible embryo rates (38% vs. 51%) were significantly higher in PICSI fertilized oocytes (p = 0.008 and p = 0.01 respectively). DISCUSSION: Our study is the largest sibling oocyte study comparing ICSI and PICSI, and the first to find a significant improvement in fertilization and embryo quality with PICSI using sibling oocytes. The fact our cohort included almost exclusively couples with previous unsuccessful IVF cycles might suggest that PICSI should be used in selected cases. CONCLUSION: PICSI improves fertilization rates and transfer eligible embryo rates in sibling oocytes in a selected study group.

'Luckily, I don't believe in statistics': survey of women's understanding of chance of success with futile fertility treatments.

RESEARCH QUESTION: Why are women who face poor prognoses for success in assisted reproductive technology (ART) treatment choosing to pursue procedures using their own eggs, despite receiving information that their chances of success are very low. DESIGN: Cross-sectional study based on an anonymous questionnaire distributed to women aged between 43 and 45 years, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel between 2015 and 2016. The main outcome measure was personal estimation of chance to achieve a live birth after the current ART treatment cycle and the cumulative estimated rate after all the treatment cycles the patient intended to undergo. RESULTS: Response rate was 70.0%, with 91 participants of mean age 43.8 ± 0.7 years. Participants estimated their delivery rates after the next ART treatment cycle at 49.0 ± 31.8% (response rate 93.4%) and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.3% (response rate 90.1%). This is significantly higher than the predicted success rates of 5% and 15%, respectively (both P < 0.001), which are based on national register data. Nearly one-half of patients rated themselves as having a better than average chance of conception (47.3%). CONCLUSION: Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many patients of advanced maternal age have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.

Elevated circulating micro-ribonucleic acid (miRNA)-200b and miRNA-429 levels in anovulatory women.

OBJECTIVE: To study the role of micro-RNA (miRNA)-200b and miRNA-429 in human ovulation and to measure their expression levels in ovulatory and anovulatory patients. DESIGN: Micro-RNA-200b and miRNA-429 expression analysis in human serum and granulosa cells at different phases of the ovulation cycle in normal cycling women and women undergoing assisted reproductive technology cycles. SETTING: University-affiliated hospital and academic research laboratory. PATIENT(S): Forty women (7 normally ovulating, 15 normally ovulating with pure male infertility factor, and 18 with polycystic ovary syndrome) were included in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The expression profile of circulating miRNAs and granulosa cells was assessed by means of real-time quantitative reverse transcription-polymerase chain reaction analysis. RESULT(S): We identified miRNA-200b and miRNA-429 in the sera of all women tested. These miRNA expression levels were elevated during the early follicular phase of the cycle compared with serum levels during the early luteal phase. Anovulatory women, diagnosed with polycystic ovary syndrome, expressed significantly higher levels of miRNA-200b and miRNA-429 compared with spontaneously ovulating women. Ovulation induction with exogenous gonadotropins during an IVF cycle reduced these levels to the levels measured in normal ovulating women. CONCLUSION(S): Our findings suggest an involvement of miRNA-200b and miRNA-429 in the pituitary regulation of human ovulation. Although it is unclear whether this altered miRNA expression profile is a cause or a result of anovulation, the levels of these molecules in the serum of anovulatory women may serve as serum biomarkers for the ovulation process.

Ovarian stimulation for oocyte cryopreservation for prevention of age-related fertility loss: one in five is a low responder.

Oocyte cryopreservation for age-related fertility loss is gaining interest considering the tendency to postpone motherhood in many societies. Little is currently known about the actual efficiency of this approach. We aimed to explore ovarian response of presumably fertile women undergoing in vitro fertilization for this indication. A total of 105 women underwent 151 stimulation cycles at mean age 37.7 ± 2.4. None had known infertility. Mean daily starting FSH dose was 371 ± 110 (225-600). Mean number of mature oocytes cryopreserved at the first completed cycle was 9.7 ± 7.5 (0-43). However, 21% of started cycles were either cancelled before egg retrieval or resulted in 0-3 mature oocytes retrieved. Therefore, women considering oocyte cryopreservation for prevention of age-related fertility decline should be encouraged to perform this procedure at younger age than, preferably before 35.

Is the quality of donated semen deteriorating? Findings from a 15 year longitudinal analysis of weekly sperm samples.

BACKGROUND: Studies suggest that global semen quality is declining, but the debate remains open owing to geographic variation. OBJECTIVES: To evaluate temporal trends of sperm parameters - namely concentration, motility and total motile sperm count - in sperm donated during the period 1995-2009. METHODS: In a retrospective longitudinal cohort study we analyzed the sperm count and motility of 2182 semen samples provided on a weekly basis by 58 young, healthy, fertile, university-educated, paid donors. RESULTS: Despite the lowering of criteria for sperm parameters satisfactory for donation that were implemented in 2004, 38% of applicants for sperm donation are now rejected based on semen quality as compared to a third of applicants 10-15 years ago (P < 0.001). If the old strict criteria were in place 88% of candidates would be rejected today (P < 0.0001). Over the study period, the average sperm parameters dropped from a concentration of 106 +/- 25 million spermatozoa/ml with 79% +/- 4.3% motility to 68 +/- 14 million/ ml with 66% +/- 4.5% motile sperm (P < 0.0001, P < 0.0001, respectively). The total motile sperm count per ejaculate also decreased, from 66.4 +/- 18.2 million to 48.7 +/- 12 million (P < 0.005). When the previous criteria were implemented for the analysis of the latest group of sperm donors, only 18% of donors had an acceptable sperm quality, with an average concentration of 87 +/- 12 million spermatozoa/ml, 73% +/- 2.6% motile sperm and total motile sperm count of 53.1 +/- 3.8 million per ejaculate - still significantly lower than 15 years ago (P= 0.01, P= 0.003, P= 0.058 respectively). CONCLUSIONS: The rapid deterioration of sperm quality among fertile semen donors is alarming and may lead to cessation of sperm donation programs.

Infertility associated with precoital ovulation in observant Jewish couples; prevalence, treatment, efficacy and side effects.

BACKGROUND: Religious (halachic*) infertility' results from precoital ovulation prior to immersion in a ritual bath (mikveh) 7 days after menstruation, as mandated by Jewish religious law. Previous authors recommended treatment with estradiol to postpone ovulation and enhance pregnancy rates. OBJECTIVES: To evaluate the prevalence of halachic infertility in an ultra-Orthodox jewish community, and assess the efficacy of estradiol treatment in postponing ovulation and increasing pregnancy rates. METHODS: We reviewed 88 cycles, of which 23 were control cycles and 65 estradiol-treated cycles, and analyzed the files of 23 women who were treated with 6 mg estradiol/day from day 1 for 5 days of the cycle. RESULTS: The prevalence of precoital ovulation in the infertile population was 21%. Most of the patients (94%) ovulated before day 13 of the cycle. A short follicular phase due to low ovarian reserve orthyroid endocrinopathy was noted in 12% of the patients. While 64% of the women reported consultation with a Rabbinate authority, 68% of the patients sought medical therapy. Estradiol postponed ovulation for at least one day in 89% of the treatment cycles. Ovulation post-mikveh occurred in 73% of estradiol-treated cycles. The pregnancy rate was 12.5% per cycle and the cumulative pregnancy rate 35% per woman. Half the patients reported spotting during estradiol-treated cycles, and this postponed coitus. CONCLUSIONS: Precoital ovulation is a major reason for infertility among observant couples attending fertility clinics. Estradiol treatment is effective in delaying ovulation and restoring fecundity; however, it causes some adverse effects that may decrease its effectiveness.

Altered endothelin expression in granulosa-lutein cells of women with polycystic ovary syndrome.

AIMS: To examine the levels of endothelin system components in granulosa lutein cells (GLCs) of women with PCOS and compare them to normally ovulating women undergoing In Vitro Fertilization (IVF). Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age. Endothelins are locally produced by endothelial and granulosa cells of the preovulatory follicle. Abnormal expression or production of endothelins may be a contributing factor in PCOS pathogenesis. MAIN METHODS: Follicular aspirates containing GLCs were obtained from PCOS and normally ovulating patients undergoing oocyte retrieval during the IVF cycle. RNA was extracted and endothelin system components were quantified using real-time PCR. GLCs were cultured in basal media for 7 days, and then challenged with various luteinizing agents (luteinizing hormone, hCG, or forskolin) for 24 h. KEY FINDINGS: In GLCs from women with PCOS, Endothelin-1 mRNA expression was elevated (2.2-fold) as compared with normally ovulating women, whereas endothelin-2 mRNA was reduced (1.8-fold). ET receptors and endothelin-converting enzyme showed the same expression levels in the two groups. In vitro modeling showed that although the steroidogenic response was preserved in GLC, endothelin expression levels were not exhibited in vitro in their original pattern. SIGNIFICANCE: Dysregulation of ovarian endothelin expression may induce a pathologic ovulation pattern characteristic of PCOS.

Infertility counseling for Orthodox Jewish couples.

OBJECTIVE: To examine traditional Jewish concepts and practices of reproduction, and define problems that may arise in members of Orthodox Jewish society that follows the Halachah (the Jewish codes of conduct). DESIGN: Expert opinion based on clinical experience. SETTING: Academic-affiliated fertility clinic situated in an observant Jewish community. PATIENT(S): Orthodox and Ultraorthodox (Haredi) couples of the Jewish community. INTERVENTIONS(S): We examined traditional Jewish concepts and practices of reproduction and defined problems that may arise in Jewish Orthodox society. MAIN OUTCOME MEASURE(S): None. RESULT(S): The concepts and practices of reproduction of Orthodox religious Jewish couples may lead to halachic subfertility and modification of the usual infertility workup. Treatments are limited to and determined largely by considerations related to religious doctrine. CONCLUSION(S): Understanding the religious, social, and cultural background of patients, particularly religious Orthodox women, enables appropriate fertility counseling and treatment.

Sex ratio is remarkably constant.

OBJECTIVE: To study whether the sex of the offspring is related to increasing parental age, gravidity, and parity, hypothesizing an altered male-to-female sex ratio with the advancing parental age. DESIGN: A large retrospective cohort study. SETTING: The study analyzed birth records of Hadassah Hebrew University Medical Center in Jerusalem from June 2003 to December 2006. PATIENT(S): 35,837 birth records were analyzed including 941 multifetal deliveries, excluding foreign inhabitants (n = 744), missing data for the main study outcome (n = 2) and parturients over 50 years to control for egg donation (n = 26). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Male-to-female sex ratio. RESULT(S): The male-to-female sex ratio of all the newborns was 1.05. This ratio did not change significantly with either maternal or paternal age. Neither gravidity nor parity affected the male-to-female ratio. The only factor that affected the regression of sex ratio was the length of gestation. CONCLUSION(S): Sex ratio at birth is remarkably constant. No association was found between parental age or birth order and neonatal sex ratio.

Monozygotic multiple gestation after intracytoplasmic sperm injection and preimplantation genetic diagnosis.

OBJECTIVE: To report a possible association between intracytoplasmic sperm injection (ICSI)-preimplantation genetic diagnosis (PGD) and monozygotic multiple gestation. DESIGN: Small case series. SETTING: In vitro fertilization unit in an academic medical center. PATIENT(S): Three patients were treated with ICSI-PGD for sexing as well as selection against a known translocation. INTERVENTION(S): Transfer of day 4 embryos to the uterus. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Two pairs of monozygotic twins and a triplet pregnancy. CONCLUSION(S): Repeated manipulation of the zona pellucida as well as extended embryo culture during ICSI-PGD treatments may result in monozygotic twin and triplet pregnancies.

[Religious (Halachic) infertility].

Reproductive concepts and practices among observant Orthodox Jews may Lead to Halachic subfertility in a significant portion of couples. According to Halachah [the Jewish code of law) sexual activity may not take place during the time a woman menstruates (Niddah) as well as for a full week thereafter (7 days of cleanliness). Coitus is allowed to resume after the woman has immersed herself in a ritual bath (mikvah). In the case of unexpected spotting or bleeding (Zavah), the woman should consult a rabbi and a doctor to determine the origin of the blood. Uterine bleeding entails that intercourse is forbidden for a minimum of 5 initial days plus 7 days thereafter. In practice, any minute bleeding or spotting, regardless of timing during the menstrual cycle, renders the woman ritually impure and invokes the stringencies of Niddah rulings. Even a physiologic occurrence such as midcycle ovulatory bleeding or spotting renders the woman Zavah and prohibits sexual intercourse at the optimal time for conception. The inability to conceive in this halachically mandated time period is not due to a biologic fault but rather to social, cultural and religious norms as defined by the rabbinate. Medically lengthening the pre-ovulatory phase is a common practice, as shortening the count of days of ritual impurity is often seen as nonnegotiable. Ethical issues concerning the role of the physician and the safety of such treatments are discussed.

Technical modification of testicular sperm extraction expedites testicular sperm retrieval.

OBJECTIVE: To determine the predictive value and the quality of supernatant sperm (SS) achieved by a simple laboratory technical modification after testicular sperm extraction (TESE). DESIGN: A retrospective analysis. SETTING: An IVF unit in a university medical center. PATIENT(S): Azoospermic patients undergoing TESE between January 2001 and December 2006. INTERVENTION(S): Before the mechanical shredding, the testicular specimen in toto was placed in medium. The medium was spun and the pellet resuspended and transferred for SS detection. Then a wet preparation of the testicular tissue was shredded roughly and inspected for tissue sperm (TS) as described. MAIN OUTCOME MEASURE(S): Detection of SS versus TS, fertilization and pregnancy rates (PR) after intracytoplasmic sperm injection (ICSI) with SS versus TS. RESULT(S): The SS was detected in all specimens where TS was eventually found, independent of their testicular pathology. When the supernatant was spermatozoa-negative, no spermatozoa were detected in the tissue. For embryos derived from ICSI the fertilization rate of SS was significantly higher than TS (52% vs. 44%), whereas the PR was comparable. CONCLUSION(S): The SS serves as an excellent predictor of TESE outcome and as a superior source for fertilization. This modified technique enables faster decision of TESE outcome and an easier switch to donor sperm when available.

The value of repeat testicular sperm retrieval in azoospermic men.

To determine the predictive value of a previous testicular biopsy to the chance of sperm retrieval in the next testicular sperm extraction (TESE) procedure, we retrospectively analyzed the outcome of past sperm collection procedures and histopathology diagnoses of patients with nonobstructive azoospermia. Repeated TESE ensured a high recovery rate (96%) when the first recovery procedure had been successful and when hypospermatogenesis was diagnosed (77%); when no spermatozoa were found on the first attempt, a repeat TESE procedure was successful in one-third of the patients.

Endometrial NK cells are special immature cells that await pregnancy.

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

Adolescent infertility--to treat or not to treat.

OBJECTIVE: To present the set of reasons for and against fertility treatment for a very young patient. DESIGN: An expert opinion based on clinical experience. SETTING: An academic-affiliated fertility clinic situated in East Jerusalem. PATIENT(S): A 16-year-old married teenager with 2 years' duration of infertility due to polycystic ovarian syndrome was referred to our infertility center after treatment with six cycles of clomiphene citrate and ovarian drilling. INTERVENTION(S): Counseling of the options of fertility treatments, weight reduction, physical exercise, metformin intake, and an additional gonadotropins-intrauterine insemination cycle with IVF backup. MAIN OUTCOME MEASURE(S): Successful pregnancy while avoiding the risk of ovarian hyperstimulation syndrome. RESULT(S): The patient conceived a single embryo and on the 30th week of gestation suffered premature uterine contractions and gave birth to a 1,330-g preterm male newborn. CONCLUSION(S): Adolescent contraception and unintended pregnancies are prevalent issues in the Western world, whereas adolescent infertility is unheard of. Early age of marriage and conception imposes tremendous dilemma to the society of reproductive endocrinologists. This important cultural issue ought to be debated regarding the age at marriage, the age at first pregnancy, and the treatment of infertility in married "minors" who need treatment. Such a debate is likely to encourage development of formal guidelines for practitioners, which would clearly be beneficial.

Acute renal failure may lead to reversible azoospermia.

OBJECTIVE: To report a possible association between azoospermia and acute renal failure. DESIGN: A case report. SETTING: An in vitro fertilization unit in an academic medical center. PATIENT(S): A patient with high-gonadotropin azoospermia and a history of acute obstructive renal failure because of bilateral renal calculi, who was referred for testicular sperm extraction. INTERVENTION(S): Deferral of the surgical procedure. MAIN OUTCOME MEASURE(S): Return of sperm into the patient's ejaculate. RESULT(S): Four months after normalization of his renal function tests, the sperm analysis showed reversal of the azoospermic state. CONCLUSION(S): Azoospermic patients with recent history of acute renal failure would be followed up for several months after renal function normalization, awaiting reappearance of sperm in the ejaculate.

[Late fertility].

Due to temporary social trends, many women elect to postpone their first pregnancy to a later stage in life. Pregnancy and labor later in life entail major risks to both the mother and the neonate. Furthermore, a large part of this population will be infertile by the time they opt to conceive, mainly because of decreasing ovarian reserve and low oocyte quality. Assessment of the fertility potential of the elderly nullipara includes clinical measurements of early follicular FSH and estradiol, clomiphene citrate test and ultrasonographic evaluation of the ovaries. A fast track step-by-step fertility evaluation is the procedure for women above 35 years of age. Only empirical treatment modalities may be offered to the elderly infertile patient, with the exception of ovum donation.

Early serum beta-human chorionic gonadotropin in pregnancies after in vitro fertilization: contribution of treatment variables and prediction of long-term pregnancy outcome.

OBJECTIVE: Low initial serum beta hCG is a good predictor of early pregnancy failure. We sought to determine the contribution of treatment variables and the predictive value of early serum beta hCG after IVF on long-term pregnancy outcome. DESIGN: A retrospective case-control study. SETTING: An academic IVF unit. PATIENT(S): Five hundred thirty-three IVF cycles performed between 1999 and 2004, which resulted in a positive serum beta hCG level (> 10 mIU/mL) on day 13 after embryo transfer (ET). INTERVENTION(S): The study group included 281 pregnancies with initial beta hCG < or = 150 mIU/mL on day 13 after ET. Randomly selected 252 IVF cycles with initial beta hCG > 150 mIU/mL comprised the control group. Characteristics of the patients and the treatment protocols were analyzed using logistic regression, Pearson's chi-square, and Fisher's exact test. MAIN OUTCOME MEASURE(S): Primary pregnancy outcome was defined as favorable when a fetal pulse was detected, testifying to a viable gestation. Unfavorable outcome referred to chemical or ectopic pregnancies, as well as spontaneous abortions. Additionally, the two groups were followed throughout gestation. Secondary pregnancy outcome was based on the following parameters: gestational age at delivery, method of delivery, and birth weight. RESULT(S): Poor primary pregnancy outcome was encountered in 64.8% of the study group and in 22.2% of the control group. Predictors of unfavorable primary pregnancy outcome were older age, use of a short protocol, and shorter than anticipated crown-rump length. No difference was found in the secondary pregnancy outcome between the groups. Preterm labor was more prevalent in the study group, but the difference did not reach statistical significance. CONCLUSION(S): Pregnancy viability can be predicted by measuring serum beta hCG as early as on day 13 after ET. Older age, use of a short protocol, and shorter than anticipated crown-rump length are associated with early pregnancy loss. Of those who reach delivery, no significant adverse outcome is anticipated in IVF pregnancies with low initial serum beta hCG.

Expression and regulation of Sprouty-2 in the granulosa-lutein cells of the corpus luteum.

Growth factor signalling has important modulatory roles in the process of human follicular growth, oocyte maturation and corpus luteum (CL) formation. Recently, Sprouty-2, an inhibitor of receptor tyrosine kinase (RTK) signalling pathway was advocated as a marker of oocyte competence in the bovine ovary. We sought to study Sprouty-2 expression and regulation in the human ovary. RT-PCR was used to detect Sprouty-2 mRNA in human granulosa-lutein cells (GLC) collected from follicular aspiration of IVF patients. The effect of epidermal and fibroblast growth factors (EGF and FGF) on Sprouty-2 mRNA expression in GLC was studied using quantitative real-time PCR. Immunohistochemistry was performed on cultured GLC, human CL and stimulated rat ovary sections. Sprouty-2 mRNA was expressed in human GLC. EGF and basic FGF, but not FGF4 and FGF10, increased Sprouty-2 mRNA expression in GLC. The Sprouty protein was localized to GLC of early and late human CL but not to the theca cell layer. Immunostaining of developing rat CL confirmed the temporal and spatial expression of Sprouty in humans. The detection of Sprouty-2 mRNA and protein in human GLC may suggest a role for Sprouty-2 during the final stages of follicle maturation and CL formation.

Reproduction concepts and practices in ancient Egypt mirrored by modern medicine.

The treasured ancient papyri provide a glimpse into understanding of common concepts and practices in ancient Egypt. The Kahun gynecological papyrus and other texts unveil the traditions of reproduction, conception and delivery. This article addresses the rationale of beliefs and practices of that era. Frequently, the reason for common traditions exercised at the time is based on medical knowledge of female anatomy and physiology during pregnancy. Surprisingly some of the remedies commonly used in ancient Egypt were recently explored and found intriguing. This paper was aimed to look at the reflection of archaic practices and concepts of ancient Egypt by the modern mirror of evidence-based medicine.