Pathways to fatherhood: clinical experiences with assisted reproductive technology in single and coupled intended fathers.

Objective: To explore the cycle characteristics and outcomes of single and coupled intended fathers (SCIFs) using assisted reproductive technology. Design: Cross-sectional study. Setting: Multicenter, fertility practices from 2016 to 2020. Patients: In this study, cycles among SCIFs with access to fertility coverage from 2016 to 2020 were included. Interventions: None. Main Outcome Measures: Our primary outcome was live birth rate. The secondary outcomes included the number of embryos transferred, miscarriage rate, and incidence of multifetal birth. Results: Five single and 39 coupled intended fathers completed an in vitro fertilization cycle with a majority using egg donation and an agency-based gestational carrier (69.7%, 83/119). In most couples, both partners wanted to serve as the sperm source (64.4%, 29/45). The vast majority (97.7%, 43/44) also used preimplantation genetic testing for aneuploidy. Among the embryo transfer (ET) cycles (n = 27), most consisted of a single euploid ET (74.07%, 20/27), whereas the remaining consisted of a double euploid ET (25.92%, 7/27). The SCIFs had high rates of success, with a live birth rate of 85.19% (23/27). A mean of 1.26 ± 0.44 embryos were transferred, with a majority resulting in singleton birth (70.37%, 19/27). Conclusions: Our study of SCIFs using assisted reproductive technology in the United States demonstrates that this population shares similar preferences for sperm source and the use of preimplantation genetic testing. Clinical outcomes suggest that this population is successful at achieving a live birth when using egg donation and a gestational carrier.

Pathways to fatherhood: evaluating the priorities of self-identified gay and bisexual men pursuing family building options.

Objective: To assess the priorities and decisions of gay and bisexual men pursuing fatherhood. Design: Cross-sectional study. Setting: Internet-based survey. Patients: Gay and bisexual men who were interested in pursuing or had previously pursued family building options. Interventions: None. Main Outcome Measures: This study aimed to assess the attitudes of respondents regarding the following: mode of achieving parenthood and the relative importance of a genetic link to offspring; the relative importance of factors considered when selecting an oocyte donor (OD); and the relative importance of factors associated with selecting a gestational carrier (GC). Access to care and financial considerations were also analyzed. Results: Of the 110 respondents, most (68.2%) desired parenthood via an OD and GC. This was consistent with 53.2% of respondents reporting that a genetic link to a child was "extremely important" or "important." Most couples (86.6%) desired to use sperm from both partners. In addition, 40.5% of respondents reported that a twin gestation would be the most ideal pregnancy outcome. Medical history was considered the most important factor when selecting an OD (83.5%), whereas pregnancy history was considered the most important selection criterion for a GC (86.2%). Furthermore, 89.1% of respondents reported that the fertility services they desired were available to them, although 33.0% reported they would have to travel to another state for care. Conclusions: Understanding the circumstances of gay and bisexual men pursuing fatherhood allows for individualized care. Since several respondents desired twin pregnancies, it is important to counsel patients regarding the risks of multiple gestation and determine the motivations for this preference.

Endometrial microbiota composition is associated with reproductive outcome in infertile patients.

BACKGROUND: Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage or no pregnancy. METHODS: Here, we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments. RESULTS: A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. CONCLUSIONS: Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies. Video Abstract.

Multicentric, prospective observational data show sperm capacitation predicts male fertility, and cohort comparison reveals a high prevalence of impaired capacitation in men questioning their fertility.

RESEARCH QUESTIONS: Can a previously defined relationship between sperm capacitation and the probability of a man generating pregnancy within three cycles, prospectively predict male fertility in diverse clinical settings? A second study asked, what is the prevalence of impaired sperm fertilizing ability in men questioning their fertility (MQF), and does this relate to traditional semen analysis metrics? DESIGN: In the multicentric, prospective observational study, data (n = 128; six clinics) were analysed to test a published relationship between the percentage of fertilization-competent, capacitated spermatozoa (Cap-Score) and probability of generating pregnancy (PGP) within three cycles of intrauterine insemination. Logistic regression of total pregnancy outcomes (n = 252) assessed fit. In the cohort comparison, Cap-Scores of MQF (n = 2155; 22 clinics) were compared with those of 76 fertile men. RESULTS: New outcomes (n = 128) were rank-ordered by Cap-Score and divided into quintiles (25-26 per group); chi-squared testing revealed no difference between predicted and observed pregnancies (P = 0.809). Total outcomes (n = 252; 128 new + 124 previous) were pooled and the model recalculated, yielding an improved fit (P < 0.001). Applying the Akaike information criterion found that the optimal model used Cap-Score alone. Cap-Scores were performed on 2155 men (with semen analysis data available for 1948). To compare fertilizing ability, men were binned by PGP (≤19%, 20-29%, 30-39%, 40-49%, 50-59%, ≥60%). Distributions of PGP and the corresponding Cap-Scores were significantly lower in MQF versus fertile men (P < 0.001). Notably, 64% of MQF with normal volume, concentration and motility (757/1183) had PGP of 39% or less (Cap-Scores ≤31), versus 25% of fertile men. CONCLUSIONS: Sperm capacitation prospectively predicted male fertility. Impaired capacitation affects many MQF with normal semen analysis results, informing diagnosis versus idiopathic infertility.

Validation of concurrent preimplantation genetic testing for polygenic and monogenic disorders, structural rearrangements, and whole and segmental chromosome aneuploidy with a single universal platform.

Preimplantation genetic testing (PGT) has been successfully applied to reduce the risk of miscarriage, improve IVF success rates, and prevent inheritance of monogenic disease and unbalanced translocations. The present study provides the first method capable of simultaneous testing of aneuploidy (PGT-A), structural rearrangements (PGT-SR), and monogenic (PGT-M) disorders using a single platform. Using positive controls to establish performance characteristics, accuracies of 97 to >99% for each type of testing were observed. In addition, this study expands PGT to include predicting the risk of polygenic disorders (PGT-P) for the first time. Performance was established for two common diseases, hypothyroidism and type 1 diabetes, based upon availability of positive control samples from commercially available repositories. Data from the UK Biobank, eMERGE, and T1DBASE were used to establish and validate SNP-based predictors of each disease (7,311 SNPs for hypothyroidism and 82 for type 1 diabetes). Area under the curve of disease status prediction from genotypes alone were 0.71 for hypothyroidism and 0.68 for type 1 diabetes. The availability of expanded PGT to evaluate the risk of polygenic disorders in the preimplantation embryo has the potential to lower the prevalence of common genetic disease in humans.

Clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos is low.

OBJECTIVE: To determine the clinically recognizable error rate with the use of quantitative polymerase chain reaction (qPCR)-based comprehensive chromosomal screening (CCS). DESIGN: Retrospective study. SETTING: Multiple fertility centers. PATIENT(S): All patients receiving euploid designated embryos. INTERVENTION(S): Trophectoderm biopsy for CCS. MAIN OUTCOME MEASURE(S): Evaluation of the pregnancy outcomes following the transfer of qPCR-designated euploid embryos. Calculation of the clinically recognizable error rate. RESULT(S): A total of 3,168 transfers led to 2,354 pregnancies (74.3%). Of 4,794 CCS euploid embryos transferred, 2,976 gestational sacs developed, reflecting a clinical implantation rate of 62.1%. In the cases where a miscarriage occurred and products of conception were available for analysis, ten were ultimately found to be aneuploid. Seven were identified in the products of conception following clinical losses and three in ongoing pregnancies. The clinically recognizable error rate per embryo designated as euploid was 0.21% (95% confidence interval [CI] 0.10-0.37). The clinically recognizable error rate per transfer was 0.32% (95% CI 0.16-0.56). The clinically recognizable error rate per ongoing pregnancy was 0.13% (95% CI 0.03-0.37). Three products of conception from aneuploid losses were available to the molecular laboratory for detailed examination, and all of them demonstrated fetal mosaicism. CONCLUSION(S): The clinically recognizable error rate with qPCR-based CCS is real but quite low. Although evaluated in only a limited number of specimens, mosaicism appears to play a prominent role in misdiagnoses. Mosaic errors present a genuine limit to the effectiveness of aneuploidy screening, because they are not attributable to technical issues in the embryology or analytic laboratories.

Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis.

OBJECTIVE: To evaluate whether persistence of pelvic pain after excision of endometriosis was associated with adenomyosis as defined by a thickened uterine junctional zone (JZ) on magnetic resonance (MR) imaging. DESIGN: Prospective clinical trial. SETTING: Government research hospital. PATIENT(S): Fifty-three women with chronic pelvic pain. INTERVENTION(S): Preoperative MR imaging to measure uterine JZ thickness, surgical excision, and pathologic diagnosis of endometriosis. Those with biopsy-proven endometriosis were randomized to raloxifene or placebo. Visual analog scale (VAS) was used to rate dysmenorrhea and nonmenstrual pain severity before surgery and 3 months later. MAIN OUTCOME MEASURE(S): Comparison of JZ thickness and pain severity before and 3 months after surgery in women with endometriosis controlling for medical treatment. RESULT(S): Forty of the 53 patients had biopsy-proven endometriosis, and 6 of these 40 women with endometriosis had a thickened JZ. Overall, dysmenorrhea at 3 months was positively correlated with preoperative JZ thickness (r = 0.47, P=.01). Dysmenorrhea pain severity showed no significant decrease in those patients whose JZ measured >or=11 mm compared with those with JZ <8 mm (P<.0001; VAS decreased 4.3 +/- 0.6), or >or=8 and <11 mm (P<.02; VAS decreased 4.8 +/- 1.3). Nonmenstrual pain severity was correlated with JZ thickness (r = 0.51, P=.004) at 3 months with a significant decrease in nonmenstrual pain only in women with a JZ <8 mm (VAS decreased 4.0 +/- 0.7, P<.0001). The association between dysmenorrhea and nonmenstrual pain reduction and thinner JZ remained after controlling for medical treatment. CONCLUSION(S): Following surgical excision of endometriosis, chronic pelvic pain was significantly more likely to persist with JZ thickness >11mm on preoperative MR imaging. This suggests that myometrial JZ abnormalities or adenomyosis may contribute to chronic pelvic pain in women with endometriosis.

Anthrax vaccine does not affect semen parameters, embryo quality, or pregnancy outcome in couples with a vaccinated male military service member.

Anthrax vaccination has been used in an effort to prevent infection should anthrax be used as a biological weapon, and widespread use has been considered in the event of another anthrax attack on American soil, but the long-term impact of anthrax vaccination on reproductive outcome is unknown. We found that exposure to the anthrax vaccine by males who were undergoing assisted reproduction did not negatively impact semen parameters, fertilization rate, embryo quality, or clinical pregnancy rates.

Estradiol stimulates expression of two human prolactin receptor isoforms with alternative exons-1 in T47D breast cancer cells.

Human prolactin receptor (hPRLR) expression is regulated by estradiol-17beta (E(2)) in vivo in animal tissues, and in vitro in normal human endometrial cells and in MCF7 human breast cancer cells. The objective of this study was to determine the effect of E(2) on the expression of two recently described hPRLR isoforms with distinct exons-1, hE1(3) and hE1(N1) that are transcribed from the generic hPIII promoter, also present in the rat and mouse, and the human-specific promoter hP(N1), respectively. Also, to determine the effect of estradiol on the hPIII promoter activity in cancer cells. T47D breast cancer cells were examined using quantitative competitive RT-PCR for the level of expression of two alternative non-coding exon-1 transcripts, hE1(3) and hE1(N1) following incubation with E(2) in presence or absence of the E(2) receptor antagonist ICI 182,780. The effects of estradiol were also evaluated in cells transiently transfected with constructs of hPIII promoter luciferase reporter gene. E(2) significantly increased the expression of both hPRLR mRNA transcripts, hE1(3) and hE1(N1). In transfection studies E(2) activated the hPIII promoter. This effect of estradiol was markedly inhibited by coincubation with the E(2) receptor antagonist. Our results demonstrate a stimulatory effect of estradiol on the expression of hPRLR mRNA species with alternative exons-1, hE1(3) and hE1(N1) possibly through activation of their corresponding promoters. The lack of a formal ERE in these promoters suggested that the effect of estradiol is mediated through association of the activated ER with relevant DNA binding transfactor(s). These findings support the role of E(2) in the regulation of hPRLR expression in human breast cancer cell lines.