hMG addition affects the change in progesterone level during IVF stimulation and LBR: a retrospective cohort study.

BACKGROUND: Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR). METHODS: Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF). RESULTS: 𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7-0.85 ng/mL (p = 0.005, 95% CI 0.635, 3.636; predicting CPR of 88.9%). The optimal range for peak P in regard to pregnancy outcome was 0.15-1.349 ng/mL (p = 0.01; 95% CI for coefficient in model 0.48-3.570). A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P (p = 0.010, 95% CI 0.035, 0.256) and smallest 𝚫P (p = 0.012, 95% CI 0.030, 0.243) during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3-0.4 [75.6% vs. 62.5% within and outside of the range, respectively, (p = 0.023, 95% CI 0.119, 1.618)]. Highest LBRs were seen within the range of 0.3-0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% (p = 0.010, 95% CI 0.176, 1.311)]. CONCLUSIONS: Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles.

The Aging Ovary and the Tales Learned Since Fetal Development.

BACKGROUND: While the term "aging" implies a process typically associated with later life, the consequences of ovarian aging are evident by the time a woman reaches her forties, and sometimes earlier. This is due to a gradual decline in the quantity and quality of oocytes which occurs over a woman's reproductive lifespan. Indeed, the reproductive potential of the ovary is established even before birth, as the proper formation and assembly of the ovarian germ cell population during fetal life determines the lifetime endowment of oocytes and follicles. In the ovary, sophisticated molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. SUMMARY: The mechanisms thought to contribute to overall aging have been summarized under the term the "hallmarks of aging" and include such processes as DNA damage, mitochondrial dysfunction, telomere attrition, genomic instability, and stem cell exhaustion, among others. Similarly, in the ovary, molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. In this review, we outline critical processes involved in ovarian aging, highlight major achievements for treatment of ovarian aging, and discuss ongoing questions and areas of debate. KEY MESSAGES: Ovarian aging is recognized as what may be a complex process in which age, genetics, environment, and many other factors contribute to the size and depletion of the follicle pool. The putative hallmarks of reproductive aging outlined herein include a diversity of plausible processes contributing to the depletion of the ovarian reserve. More research is needed to clarify if and to what extent these putative regulators do in fact govern follicle and oocyte behavior, and how these signals might be integrated in order to control the overall pattern of ovarian aging.

Reproductive and Fertility Knowledge and Attitudes Among Transgender and Gender-Expansive Youth: A Replication and Extension.

Purpose: This study sought to replicate and expand a previous pilot investigation of reproductive knowledge, attitudes toward fertility and parenthood, and sources of information on these topics among transgender and gender-expansive (TGE) youth. Methods: The Yale Pediatric Gender Program (YPGP) Reproductive Knowledge and Experiences Survey (YPGP-RKES) was administered to 70 TGE adolescents receiving care at an interdisciplinary clinic providing gender-affirming health care at an academic medical center. Data gathered included sources of information on reproduction and fertility, concerns about future parenthood and reproduction, and interest in different types of parenthood. Results: Over a third (39.1%) of participants reported it was important to them to have a child one day, while only a small proportion (23.2%) reported an interest in biological parenthood. A plurality of participants (37.3%) reported at least one concern about future fertility. The number of reproductive concerns did not differ by age or treatment (puberty blockers or gender-affirming hormones vs. no treatment) status. With respect to needs for more information and sources of information, most (56.5%) participants received information about fertility issues before this study, with the most cited source of information being online research. Conclusions: The current study replicated and extended previous findings on the reproductive attitudes and knowledge of TGE adolescents. Understanding the informational needs and priorities of adolescent TGE patients presenting for medical treatment will allow providers to give more robust patient education. This will, in turn, facilitate patients' ability to provide fully informed consent for treatment that aligns with their fertility and reproductive priorities and goals.

Expression and T cell regulatory action of the PD-1 immune checkpoint in the ovary and fallopian tube.

PROBLEM: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract. METHOD OF STUDY: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ). RESULTS: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions. CONCLUSION: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.

Aberrant H19 Expression Disrupts Ovarian Cyp17 and Testosterone Production and Is Associated with Polycystic Ovary Syndrome in Women.

As one of the most common endocrine disorders affecting women, polycystic ovary syndrome (PCOS) is associated with serious conditions including anovulation, endometrial cancer, infertility, hyperandrogenemia, and an increased risk for obesity and metabolic derangements. One contributing etiology to the pathophysiology of hyperandrogenemia associated with PCOS is an intrinsic alteration in ovarian steroidogenesis, leading to enhanced synthesis of androgens including testosterone. Studies have suggested that the increased testosterone synthesis seen in PCOS is driven in part by increased activity of CYP17A1, the rate-limiting enzyme for the formation of androgens in the gonads and adrenal cortex, which represents a critical factor driving enhanced testosterone secretion in PCOS. In this work, we evaluated the hypothesis that dysregulation of the noncoding RNA H19 results in aberrant CYP17 and testosterone production. To achieve this, we measured Cyp17 in ovarian tissues of H19 knockout mice, and quantified serum testosterone levels, in comparison with wild-type controls. We also evaluated circulating and ovarian H19 expression and correlated results with the presence or absence of PCOS in a group of women undergoing evaluation and treatment for infertility. We found that the loss of H19 in a mouse model results in decreased ovarian Cyp17, along with decreased serum testosterone in female mice. Moreover, utilizing serum samples and cumulus cells from women with PCOS, we showed that circulating and ovarian levels of H19 are increased in women with PCOS compared to controls. Findings from our multimodal experimental strategy, involving both a mouse model of dysregulated H19 expression and clinical serum and ovarian cellular samples from women with PCOS, suggest that the loss of H19 may disrupt androgen production via a Cyp17-mediated mechanism. Conversely, excess H19 may play a role in the pathogenesis of PCOS-associated hyperandrogenemia.

A multisociety organizational consensus process to define guiding principles for acute perioperative pain management.

The US Health and Human Services Pain Management Best Practices Inter-Agency Task Force initiated a public-private partnership which led to the publication of its report in 2019. The report emphasized the need for individualized, multimodal, and multidisciplinary approaches to pain management that decrease the over-reliance on opioids, increase access to care, and promote widespread education on pain and substance use disorders. The Task Force specifically called on specialty organizations to work together to develop evidence-based guidelines. In response to this report's recommendations, a consortium of 14 professional healthcare societies committed to a 2-year project to advance pain management for the surgical patient and improve opioid safety. The modified Delphi process included two rounds of electronic voting and culminated in a live virtual event in February 2021, during which seven common guiding principles were established for acute perioperative pain management. These principles should help to inform local action and future development of clinical practice recommendations.

What is optimal timing of warming for transferring vitrified cleavage stage of day 3 slow-growing embryos? A cohort retrospective study.

PURPOSE: To evaluate optimal warming time, the early warming or the routine warming time, for transferring vitrified-warmed and cultured overnight cleavage stage of the slow-growing embryos on day 3 in frozen embryo transfer (FET) cycle. METHODS: This was a retrospective cohort study from January 2017 to July 2018. A total of 705 FET patients aged < 40 years were included and 1486 embryos were formed, of which 1366 embryos were eventually transferred. RESULTS: For slow-growing embryos, the clinical pregnancy rate of early warming group [152/468 (32.5%)] was significantly higher than that of routine warming group (55/235 (23.4%)) [OR 1.39 (CI 1.06-1.81), p = 0.01], while there was no statistically significant difference in pregnancy loss in early warming group [39/170 (22.9%)] versus in routine warming group [16/62 (25.8%)] [OR 0.89 (CI 0.53-1.47), p = 0.65]. CONCLUSION: For slow-growing embryos, higher pregnancy outcomes were shown in early warming strategy as compared to the routine warming, which suggested that the improvement of endometrium-embryo synchronism may correct the time difference brought by the slow-growing embryos.

Laser-assisted hatching zona thinning does not improve the pregnancy outcomes of poor-quality blastocysts in frozen-thawed embryo transfer cycle: a retrospective cohort study.

It had been suggested, after facilitating the hatching process, improved pregnancy outcomes could be attained in embryos with thick and hard zona. This study aimed to determine the effect of zona thinning on pregnancy outcomes in poor-quality frozen-thawed blastocysts. This retrospective study included 230 women (≤ 40 years) who underwent frozen embryo transfer of poor-quality blastocysts (scored < 3BB). In total, 105 patients were in the assisted hatching group in which the zona was thinned by laser before transfer and 125 patients were in the control group in which the blastocysts were non-manipulated. Patients' demographics, cycle characteristics, and pregnancy outcomes were compared between the assisted hatching group and the control group. Further, regression analysis was applied to test the correlation between assisted hatching and live birth. All parameters in the patients' demographic characteristics and the cycle's characteristics were not significantly different between two groups. As for pregnancy outcomes, the second trimester pregnancy loss was significantly higher in the assisted hatching group (P = 0.035). Other pregnancy outcomes, including implantation rate, clinical pregnancy rate, biochemical miscarriage rate, the first trimester pregnancy loss, ongoing pregnancy rate, and live birth rate were comparable between two groups. The logistic regression analysis demonstrated no association between live birth and assisted hatching (univariate, OR = 0.787, P > 0.05; multivariate, OR = 0.652, P > 0.05), and the area under the receiver operating characteristic curve of the regression model was almost 0.7. It suggested that zona thinning may not be supposed to perform on poor-quality, frozen-thawed blastocysts. The indications of assisted hatching were still needed to further investigate.

Multifaceted Approach to Evaluation in a Pediatric and Adolescent Gynecology Rotation for Medical Students.

STUDY OBJECTIVE: We evaluated whether and to what extent a novel medical student rotation in pediatric and adolescent gynecology (PAG) increases clinical knowledge and skills and meets student needs and expectations. DESIGN: Constructivist prospective pre-post study and post-rotation student survey SETTING: Academic medical center PARTICIPANTS: Pilot study of 9 medical students, which represents the entire population of those who completed the rotation. INTERVENTIONS: Four-week clinical rotation in PAG MAIN OUTCOME MEASURES: Changes in clinical knowledge were measured by a pre- and post-intervention multiple-choice assessment, and clinical skills were assessed before and after the intervention using entrustable professional activities (EPAs); these data were analyzed with paired Student's t tests. Student evaluations of the rotation were measured through an anonymous, end-of-rotation, closed- and open-ended survey and were analyzed using descriptive statistics. RESULTS: A statistically significant increase in clinical knowledge was observed post-rotation, with a mean pretest score of 67.0% (standard deviation [SD] 1.7%) and a mean posttest score of 75.2% (SD 3.2%, P = 0.02). Statistically significant increases were observed for all EPAs between the first and final day of the rotation. Eight students who completed the post-rotation survey rated the rotation favorably (5 on a scale from 1 to 5). CONCLUSION: A multipronged evaluation showed that a new PAG clinical rotation significantly increased medical students' clinical skills and knowledge. This multifaceted evaluation method provides valuable insights to educators on how best to tailor a rotation to individual learners' levels of clinical skills and knowledge. If comparable rotations could be instituted and similarly evaluated in other medical schools, a noticeable knowledge/skill gap among trainees might be addressed.

Diagnosis and Management of Infertility: A Review.

IMPORTANCE: In the US, approximately 12.7% of reproductive age women seek treatment for infertility each year. This review summarizes current evidence regarding diagnosis and treatment of infertility. OBSERVATIONS: Infertility is defined as the failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse. Approximately 85% of infertile couples have an identifiable cause. The most common causes of infertility are ovulatory dysfunction, male factor infertility, and tubal disease. The remaining 15% of infertile couples have "unexplained infertility." Lifestyle and environmental factors, such as smoking and obesity, can adversely affect fertility. Ovulatory disorders account for approximately 25% of infertility diagnoses; 70% of women with anovulation have polycystic ovary syndrome. Infertility can also be a marker of an underlying chronic disease associated with infertility. Clomiphene citrate, aromatase inhibitors such as letrozole, and gonadotropins are used to induce ovulation or for ovarian stimulation during in vitro fertilization (IVF) cycles. Adverse effects of gonadotropins include multiple pregnancy (up to 36% of cycles, depending on specific therapy) and ovarian hyperstimulation syndrome (1%-5% of cycles), consisting of ascites, electrolyte imbalance, and hypercoagulability. For individuals presenting with anovulation, ovulation induction with timed intercourse is often the appropriate initial treatment choice. For couples with unexplained infertility, endometriosis, or mild male factor infertility, an initial 3 to 4 cycles of ovarian stimulation may be pursued; IVF should be considered if these approaches do not result in pregnancy. Because female fecundity declines with age, this factor should guide decision-making. Immediate IVF may be considered as a first-line treatment strategy in women older than 38 to 40 years. IVF is also indicated in cases of severe male factor infertility or untreated bilateral tubal factor. CONCLUSIONS AND RELEVANCE: Approximately 1 in 8 women aged 15 to 49 years receive infertility services. Although success rates vary by age and diagnosis, accurate diagnosis and effective therapy along with shared decision-making can facilitate achievement of fertility goals in many couples treated for infertility.

Updates on molecular and environmental determinants of luteal progesterone production.

Progesterone, a critical hormone in reproduction, is a key sex steroid in the establishment and maintenance of early pregnancy and serves as an intermediary for synthesis of other steroid hormones. Progesterone production from the corpus luteum is a tightly regulated process which is stimulated and maintained by multiple factors, both systemic and local. Multiple regulatory systems, including classic mediators of gonadotropin stimulation such as the cAMP/PKA pathway and TGFß-mediated signaling pathways, as well as local production of hormonal factors, exist to promote granulosa cell function and physiological fine-tuning of progesterone levels. In this manuscript, we provide an updated narrative review of the known mediators of human luteal progesterone and highlight new observations regarding this important process, focusing on studies published within the last five years. We will also review recent evidence suggesting that this complex system of progesterone production is sensitive to disruption by exogenous environmental chemicals that can mimic or interfere with the activities of endogenous hormones.

Emerging roles for noncoding RNAs in female sex steroids and reproductive disease.

The "central dogma" of molecular biology, that is, that DNA blueprints encode messenger RNAs which are destined for translation into protein, has been challenged in recent decades. In actuality, a significant portion of the genome encodes transcripts that are transcribed into functional RNA. These noncoding RNAs (ncRNAs), which are not transcribed into protein, play critical roles in a wide variety of biological processes. A growing body of evidence derived from mouse models and human data demonstrates that ncRNAs are dysregulated in various reproductive pathologies, and that their expression is essential for female gametogenesis and fertility. Yet in many instances it is unclear how dysregulation of ncRNA expression leads to a disease process. In this review, we highlight new observations regarding the roles of ncRNAs in the pathogenesis of disordered female steroid hormone production and disease, with an emphasis on long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). We will focus our discussion in the context of three ovarian disorders which are characterized in part by altered steroid hormone biology - diminished ovarian reserve, premature ovarian insufficiency, and polycystic ovary syndrome. We will also discuss the limitations and challenges faced in studying noncoding RNAs and sex steroid hormone production. An enhanced understanding of the role of ncRNAs in sex hormone regulatory networks is essential in order to advance the development of potential diagnostic markers and therapeutic targets for diseases, including those in reproductive health. Our deepened understanding of ncRNAs has the potential to uncover new applications and therapies; however, in many cases, the next steps will involve distinguishing critical ncRNAs from those which are merely changing in response to a particular disease state, or which are altogether unrelated to disease pathophysiology.

Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling.

The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBß, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBß. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.

The relationship between H19 and parameters of ovarian reserve.

CONTEXT: The H19 long noncoding RNA (lncRNA) belongs to a highly conserved, imprinted gene cluster involved in embryonic development and growth control. We previously described a novel mechanism whereby the Anti-mullerian hormone (Amh) appears to be regulated by H19. However, the relationship between circulating H19 and markers of ovarian reserve including AMH not been investigated. OBJECTIVE: To determine whether H19 expression is altered in women with decreased ovarian reserve. DESIGN: Experimental study. SETTING: Yale School of Medicine (New Haven, USA) and Gazi University School of Medicine (Ankara, Turkey). PATIENTS OR OTHER PARTICIPANTS: A total of 141 women undergoing infertility evaluation and treatment. INTERVENTION: Collection of discarded blood samples and cumulus cells at the time of baseline infertility evaluation and transvaginal oocyte retrieval, respectively. MAIN OUTCOME MEASURE: Serum and cumulus cell H19 expression. RESULTS: Women with diminished ovarian reserve (as determined by AMH) had significantly lower serum H19 expression levels as compared to controls (p < 0.01). Serum H19 was moderately positively correlated with serum AMH. H19 expression was increased 3.7-fold in cumulus cells of IVF patients who demonstrated a high response to gonadotropins, compared to low responders (p < 0.05). CONCLUSION: In this study, we show that downregulation of H19 in serum and cumulus cells is closely associated with decreased ovarian reserve, as measured by decreased AMH levels and reduced oocyte yield at oocyte retrieval. Further study with expanded sample sizes is necessary to determine whether H19 may be of use as a novel biomarker for diminished ovarian reserve.

Efficacy of intrauterine perfusion of peripheral blood mononuclear cells (PBMC) for infertile women before embryo transfer: meta-analysis.

This meta-analysis was intended to evaluate the effects of intrauterine perfusion of peripheral blood mononuclear cells (PBMC) on the pregnancy outcomes including clinical pregnancy rates, embryo implantation rates, live birth rates and miscarriage rates of infertile women who were undergoing in vitro fertilisation (IVF) treatment. By searching Pubmed, Embase database, five articles meeting the inclusion criteria were included, and 1173 women were enrolled (intrauterine PBMC group: n = 514; NO-PBMC group: n = 659). For the entire IVF/ICSI population and one or two embryo transfer failure patients, there was no significant difference in endometrial thickness, embryo implantation rates, live birth rates, and miscarriage rates between the PBMC group and NO-PBMC group. Although the clinical pregnancy rates of the PBMC group were higher than that of the NO-PBMC group, the confidence interval was close to the line of unity. As for the patients with three or more implantation failures, the clinical pregnancy rates, embryo implantation rates and live birth rates were much higher in the PBMC group than that of the NO-PBMC group. In summary, current evidence suggests that intrauterine perfusion of PBMC can significantly improve pregnancy outcomes in patients who have three or more implantation failures.Impact statementWhat is already known on this subject? An increasing number of studies have shown that immune cells play an important role in embryo transfer. There is no reliable evidence to confirm the clinical efficacy of intrauterine perfusion of PBMC.What do the results of this study add? The current evidence suggests that intrauterine perfusion of PBMC can significantly improve pregnancy outcomes in patients who have three or more implantation failures.What are the implications of these findings for clinical practice and/or further research? To the best of our knowledge, this meta-analysis is the first to evaluate the effect of intrauterine perfusion of PBMC on pregnancy outcomes before embryo transfer. Our study indicated that intrauterine perfusion of PBMC significantly increased clinical pregnancy rates, embryo implantation rates, and live birth rates in patients who failed more than three implants.

H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas.

Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting ~80% of women, and symptomatic in 25%, UFs bring tremendous suffering and are an economic burden worldwide; they cause severe pain and bleeding, and are the leading cause of hysterectomy. Yet, UFs are severely understudied with few effective treatment options available; those that are available frequently have significant side effects such as menopausal symptoms. Recently, integrated genome-scale studies have revealed mutations and fibroid subtype-specific expression changes in key driver genes, with MED12 and HMGA2 together contributing to nearly 90% of all UFs, but their regulation of expression is poorly characterized. Here we report that the expression of H19 long noncoding RNA (lncRNA) is aberrantly increased in UFs. Using cell culture and genome-wide transcriptome and methylation profiling analyses, we demonstrate that H19 promotes expression of MED12, HMGA2, and key ECM-remodeling genes via multiple mechanisms including a new class of epigenetic modification by TET3. Our results mark the first example of an evolutionarily conserved lncRNA in pathogenesis of UFs and regulation of TET expression. Given the link between a H19 single-nucleotide polymorphism (SNP) and increased risk and tumor size of UFs, and the existence of multiple fibroid subtypes driven by key pathway genes regulated by H19, we propose a unifying mechanism for pathogenesis of uterine fibroids mediated by H19 and identify a pathway for future exploration of novel target therapies for uterine leiomyomas.

Absence of the long noncoding RNA H19 results in aberrant ovarian STAR and progesterone production.

The steroidogenic acute regulatory protein (STAR) governs the rate-limiting step in steroidogenesis, and its expression varies depending on the needs of the specific tissue. It is well known that tight control of steroid production is essential for multiple processes involved in reproduction. We recently showed that Star is regulated at the posttranscriptional level in vitro by H19 and let-7. Here we demonstrate that this novel regulatory mechanism is functional in vivo, regulated by cAMP, and that loss of H19 not only disrupts ovarian STAR but also results in altered progesterone production in an H19KO mouse model. This work further strengthens the possibility that noncoding-RNA-mediated regulation of STAR may play an important role in the regulation of steroid hormone production, and contributes further to our understanding of the many ways in which this important gene is regulated.

Translational activation of maternally derived mRNAs in oocytes and early embryos and the role of embryonic poly(A) binding protein (EPAB).

Transcription ceases upon stimulation of oocyte maturation and gene expression during oocyte maturation, fertilization, and early cleavage relies on translational activation of maternally derived mRNAs. Two key mechanisms that mediate translation of mRNAs in oocytes have been described in detail: cytoplasmic polyadenylation-dependent and -independent. Both of these mechanisms utilize specific protein complexes that interact with cis-acting sequences located on 3'-untranslated region (3'-UTR), and both involve embryonic poly(A) binding protein (EPAB), the predominant poly(A) binding protein during early development. While mechanistic details of these pathways have primarily been elucidated using the Xenopus model, their roles are conserved in mammals and targeted disruption of key regulators in mouse results in female infertility. Here, we provide a detailed account of the molecular mechanisms involved in translational activation during oocyte and early embryo development, and the role of EPAB in this process.