Inhibition of NFAT promotes loss of tissue resident uterine natural killer cells and attendant pregnancy complications in humans.

Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced endometrial NK cells and altered pregnancy phenotypes. We further show that the NK reduction in UTx is due to impaired transcriptional programming of NK tissue residency due to blockade of the transcription factor nuclear factor of activated T cells (NFAT). NFAT-dependent genes played a role in multiple molecular circuits governing tissue residency in uNKs, including early residency programs involving AP-1 transcription factors as well as TGFß-mediated upregulation of surface integrins. Collectively, our data identify a previously undescribed role for NFAT in uterine NK tissue residency and provide novel mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue resident NK subsets in humans. One Sentence Summary: Role of NFAT in uterine NK cell tissue residency.

Using Teamwork to Bridge the Adolescent and Young Adult Gap.

PURPOSE: Individuals diagnosed with cancer age between 15 and 39 years (adolescents and young adults [AYAs]) have not seen improvement in survival compared with children or older adults; clinical trial accrual correlates with survival. Unique unmet needs among AYAs related to psychosocial support and fertility preservation (FP) are associated with health-related quality of life. METHODS: We enhanced existing structures and leveraged faculty/staff across pediatric/adult oncology to create novel teams focused on AYA (age 15-39 years) care at a single center, with minimal dedicated staff and no change to revenue streams. We aimed to influence domains shown to drive survival and health-related quality of life: clinical trial enrollment, physician/staff collaboration, psychosocial support, and FP. We captured metrics 3 months after patients presented to the institution and compared them before/after Program implementation using descriptive statistics. RESULTS: Among 139 AYAs (age 15-39 years) from the pre-Program era (January 2016-February 2019: adult, n = 79; pediatric, n = 60), and 279 from the post-Program era (February 2019-March 2022: adult, n = 215; pediatric, n = 64), there was no change in clinical trial enrollment(P ≥ .3), whereas there was an increase in the proportion of AYAs referred for supportive care and psychology (pediatric: P ≤ .02; adult: P ≤ .001); whose oncologists discussed FP (pediatric: 15% v 52%, P < .0001; adult: 37% v 50%, P = .0004); and undergoing FP consults (pediatric: 8% v39%, P < .0001; adult 23% v 38%, P = .02). CONCLUSION: This team-based framework has effected change in most targeted domains. To affect all domains and design optimal interventions, it is crucial to understand patient-level and facility-level barriers/facilitators to FP and clinical trial enrollment.

Investigation of racial disparities in semen parameters among white, black, and Asian men.

BACKGROUND: Male factor infertility is the primary cause of infertility in 20% of couples. Primary evaluation of male factor infertility includes a semen analysis (SA). The World Health Organization (WHO) criteria are widely used to interpret SA. However, the current normative values seen in WHO criteria have led to research showing racial disparities in prevalence of abnormal SA. OBJECTIVE: To assess the relationship between different self-reported racial groups and rates of abnormal SA. MATERIALS & METHODS: We conducted a retrospective cohort study at a single large tertiary care facility. All men who underwent a SA for evaluation of suspected male infertility, unexplained infertility, intrauterine insemination, and in vitro fertilization between January 1, 2017 and December 31, 2019, were considered for inclusion in the study. Exclusion criteria were unreported race or ethnicity, SA for fertility preservation only, history of varicocele or testicular surgery, chromosomal abnormalities, congenital bilateral absence of vas deferens, prior testosterone use, or prior exposure to chemotherapy and/or radiation. Samples obtained via testicular sperm extraction or post-ejaculatory urine collection, or those analyzed ≥1 h from ejaculation, were also excluded. RESULTS: 872 SAs were identified, of which 615 met inclusion criteria, yielding 384 normal and 231 abnormal results. Only race (p < 0.0001) and age (p = 0.002) were statistically significant. Black men had the highest rate of abnormal SA (54%) and were significantly more likely to have lower semen volume, sperm concentration, total sperm count, percent motile sperm, and total motile sperm (p < 0.05). In a logistic regression model, controlling for age and using White Non-Hispanic as the referent group, only Blacks had lower odds for a normal SA (OR = 0.41, 95% CI 0.28, 0.60). DISCUSSION AND CONCLUSIONS: Black men are more likely to have an abnormal SA based on the 2010 WHO criteria. Black men seeking infertility treatment should be educated on the incidence of abnormal SA and actively seek infertility evaluation.

To treat or not to treat: perceptions of the initial American Society for Reproductive Medicine COVID-19 recommendations among women's health providers.

PURPOSE: The objective of this study was to evaluate the perception of the initial ASRM COVID-19 recommendations for infertility treatment held by women's health providers within varying subspecialties, as well as their attitudes toward pregnancy and fertility during this time. METHODS: An electronic survey was sent to all women's healthcare providers, including physicians, mid-level providers and nurses, in all subspecialties of obstetrics and gynaecology (Ob/Gyn) at a large tertiary care university-affiliated hospital. RESULTS: Of the 278 eligible providers, the survey response rate was 45% (n = 127). Participants represented 8 Ob/Gyn subspecialties and all professional levels. Participants age 18-30 years were significantly more likely to feel that women should have access to infertility treatment despite the burden level of COVID-19 in respective community/states (p = 0.0058). Participants within the subspecialties of general Ob/Gyn, maternal foetal medicine and gynecologic oncology were significantly more likely to disagree that all women should refrain from planned conception during the COVID-19 pandemic, in comparison to those in urogynecology and reproductive endocrinology and infertility (p = 0.0003). CONCLUSIONS: Considering the immediate and unknown long-term impact of the COVID-19 pandemic on fertility care delivery, a better understanding of perceptions regarding infertility management during this time is important. Our study shows overall support for the initial ASRM recommendations, representing a wide spectrum of women's health providers.

Mitochondria in Ovarian Aging and Reproductive Longevity.

Mitochondrial dysfunction is one of the hallmarks of aging. Consistently mitochondrial DNA (mtDNA) copy number and function decline with age in various tissues. There is increasing evidence to support that mitochondrial dysfunction drives ovarian aging. A decreased mtDNA copy number is also reported during ovarian aging. However, the mitochondrial mechanisms contributing to ovarian aging and infertility are not fully understood. Additionally, investigations into mitochondrial therapies to rejuvenate oocyte quality, select viable embryos and improve mitochondrial function may help enhance fertility or extend reproductive longevity in the future. These therapies include the use of mitochondrial replacement techniques, quantification of mtDNA copy number, and various pharmacologic and lifestyle measures. This review aims to describe the key evidence and current knowledge of the role of mitochondria in ovarian aging and identify the emerging potential options for therapy to extend reproductive longevity and improve fertility.

Advanced Imaging in Female Infertility.

PURPOSE OF REVIEW: This review highlights the role of imaging in the diagnosis and management of reproductive disorders. The additional information that imaging studies can contribute to reproductive medicine is emphasized, including the role of pelvic ultrasonography (US, including sonohysterography and contrast-enhanced hysterosalpingosonography), hysterosalpingography (HSG), and magnetic resonance imaging (MRI) of the female reproductive tract. In addition, the implications of congenital causes of infertility on the urinary tract in females are reviewed. While the evaluation of infertility in women is initially focused on the assessment of ovulation via serum hormone levels, imaging plays a role in evaluating other causes of infertility. Recent research in this field focuses on the establishment of a comprehensive single imaging study for the assessment of female reproductive disorders. Two proposed methods are MR hysterosalpingography and Fertiliscan, a combination of high-quality 3D ultrasound and assessment of tubal patency with hysterosalpingo-foam-sonography, though more research is needed to determine the risks and benefits of each method, as well as their reliability.

Evidence-based approach to unexplained infertility: a systematic review.

OBJECTIVE: To summarize the available evidence for the efficacy of various treatments for unexplained infertility. DESIGN: Systematic review. SETTING: Not applicable. PATIENT(S): Patients aged 18-40 years with unexplained infertility. INTERVENTION(S): Clomiphene citrate, letrozole, timed intercourse, IUI, gonadotropins, IVF, and IVF-intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate. RESULT(S): Thirteen studies with a total of 3,081 patients were identified by systematic search and met inclusion criteria. The available literature demonstrates that expectant management may be comparable to treatment with clomiphene and timed intercourse or IUI. Clomiphene may be more effective than letrozole, and treatment with gonadotropins seems more effective, albeit with significantly higher risk of multiple gestations than either oral agent. On the basis of current data, IVF, with or without intracytoplasmic sperm injection, is no more effective than gonadotropins with IUI for unexplained infertility. CONCLUSION(S): Adequately powered, randomized controlled trials that compare all of the available treatments for unexplained infertility are needed. Until such data are available, clinicians should individualize the management of unexplained infertility with appropriate counseling regarding the empiric nature of current treatment options including IVF.