Differential Gene Regulation of the Human Blastocyst Trophectoderm and Inner Cell Mass by Progesterone.

Knowledge of action of progesterone (P4) on the human preimplantation embryo is lacking. The objective of this study was to determine expression of a mitochondrial P4 receptor (PR-M) in the trophectoderm (TE) and the inner cell mass (ICM) of the human blastocyst and to determine P4-induced gene expression during growth from the cleavage to the blastocyst stage. Previously cryopreserved cleavage stage embryos were treated with P4 (10-6 M) or vehicle until blastocyst development. Cells from the TE and the ICM of dissected euploid embryos underwent RNA-seq analysis, while other embryos were used for analysis of nuclear PR (nPR) and PR-M expression.PR-M expression was confirmed in the TE, the ICM, and a human embryonic stem cell line (HESC). Conversely, nPR expression was absent in the TE and the ICM with low expression in the HESC line. RNA-seq analysis revealed P4 effects greater in the TE with 183 significant pathway changes compared to 27 in the ICM. The TE response included significant upregulation of genes associated with DNA replication, cell cycle phase transition and others, exemplified by a 7.6-fold increase in the cell proliferation gene, F-Box Associated Domain Containing. The majority of ICM pathways were downregulated including chromosome separation, centromere complex assembly and chromatin remodeling at centromere. This study confirms that human blastocysts express PR-M in both the TE and the ICM, but lack expression of nPR. P4-induced gene regulation differs greatly in the two cell fractions with the predominant effect of cell proliferation in the TE and not the ICM.

What predicts durable symptom relief of uterine fibroids treated with MRI-guided focused ultrasound? A multicenter trial in 8 academic centers.

OBJECTIVE: To identify variables predictive of durable clinical success after MRI-guided focused ultrasound (MRgFUS) treatment of uterine fibroids. MATERIALS AND METHODS: In this prospective, multicenter trial, 99 women with symptomatic uterine fibroids were treated using MRgFUS. Pelvic MRI was obtained at baseline and treatment day. The Uterine Fibroid Symptom-Quality of Life questionnaire was used to calculate a symptom severity score (SSS) at baseline and 6, 12, 24, and 36 months following treatment. Clinical, imaging, and treatment variables were correlated with symptom reduction sustained through the 12- and 24-month time points using univariable and multivariable logistic regression analyses. A novel parameter, the ratio of non-perfused volume to total fibroid load (NPV/TFL), was developed to determine association with durable outcomes. RESULTS: Post-treatment, mean symptom severity decreased at the 6-, 12-, 24-, and 36-month follow-ups (p < 0.001, all time points). In univariable analysis, three variables predicted treatment success (defined by ≥ 30-point improvement in SSS) sustained at both the 12-month and 24-month time points: increasing ratio of NPV/TFL (p = 0.002), decreasing total fibroid load (p = 0.04), and the absence of T2-weighted Funaki type 2 fibroids (p = 0.02). In multivariable analysis, the NPV/TFL was the sole predictor of durable clinical success (p = 0.01). Patients with ratios below 30% had less improvement in SSS and lacked durable clinical response compared with those between 30-79 (p = 0.03) and ≥ 80% (p = 0.01). CONCLUSION: Increased non-perfused volume relative to total fibroid volume was significantly associated with durable reduction of symptoms of abnormal uterine bleeding and bulk bother. CLINICAL RELEVANCE STATEMENT: Patient selection for sustained clinical benefit should emphasize those with likelihood of achieving high ablation ratios, as determined by imaging (e.g., device access, Funaki type) and by considering the total fibroid load, not just the primary symptomatic fibroid. TRIAL REGISTRATION: Clinical trial ID: NCT01285960. KEY POINTS: • Patient selection/treatment approach associated with durable symptom relief in MRI-guided focused ultrasound ablation of uterine fibroids remains unclear. • The ablation ratio, non-perfused volume/total fibroid volume, was positively associated with sustained symptom relief in both bleeding and bulk bother at 1- and 2-year follow-ups. • Selecting patients with imaging features that favor a high ratio of ablation to total fibroid load (including non-targeted fibroids) is the main factor in predicting durability of symptom relief after uterine fibroid treatment.

Direct-to-consumer fertility testing: utilization and perceived utility among fertility patients and reproductive endocrinologists.

RESEARCH QUESTION: What is the utilization of direct-to-consumer fertility tests (DTCFT) among fertility patients? How does the perceived utility of DTCFT differ between patients and reproductive endocrinologists (REI)? DESIGN: Infertility patients visiting the Duke Fertility Center between December 2020 and December 2021 were sent an electronic invitation to participate in a patient survey. Members of the Society of Reproductive Endocrinology and Infertility were also sent e-mail invitations to participate in the REI survey. DTCFT were defined as tests not ordered by a physician or performed at a physician's office, including calendar methods of ovulation prediction, urinary ovulation prediction kits, basal body temperature (BBT) monitoring, hormone analysis, ovarian reserve testing and semen analysis. Patients and REI were asked how likely they were to recommend a given DTCFT, on a 0-10 Likert scale. RESULTS: In total, 425 patients (response rate 50.5%) and 178 REI (response rate 21.4%) completed the surveys. Patients reported the utilization of calendar methods of ovulation prediction (83.8%), urinary ovulation prediction (78.8%), BBT monitoring (30.8%), hormone analysis (15.3%), semen analysis (10.1%) and ovarian reserve testing (9.2%). REI rated the utility of all DTCFT significantly lower than patients did (average discordance -4.2, P < 0.001), except for urinary ovulation prediction, which REI gave a significantly higher score (discordance +1.0, P < 0.001). Prior pregnancy was significantly associated with home ovulation prediction utilization among patients (adjusted odds ratio 3.21, 95% confidence interval 1.2-9.83). CONCLUSIONS: Methods of ovulation prediction are commonly used by fertility patients. Significant discordance exists in the perceived utility of DTCFT between patients and REI. Patient education and guidelines are needed to better inform individuals considering DTCFT.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

BACKGROUND: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.

Reproductive Functions of the Mitochondrial Progesterone Receptor (PR-M).

Classic transcriptional regulation by progesterone via the nuclear progesterone receptors A and B (PR-A, PR-B) has been recognized for decades. Less attention has been given to a mitochondrial progesterone receptor (PR-M) responsible for non-nuclear activities. PR-M is derived from the progesterone receptor (PR) gene from an alternate promoter with the cDNA encoding a unique 5' membrane binding domain followed by the same hinge and hormone-binding domain of the nPR. The protein binds to the mitochondrial outer membrane and functions to increase cellular respiration via increased beta-oxidation and oxidative phosphorylation with resulting adenosine triphosphate (ATP) production. Physiologic activities of PR-M have been studied in cardiac function, spermatozoa activation, and myometrial growth, all known to respond to progesterone. Progesterone via PR-M increases cardiomyocyte cellular respiration to meet the metabolic demands of pregnancy with increased contractility. Consequential gene changes associated with PR-M activation include production of proteins for sarcomere development and for fatty acid oxidation. Regarding spermatozoa function, progesterone via PR-M increases cellular energy production necessary for progesterone-dependent hyperactivation. A role of progesterone in myometrial and leiomyomata growth may also be explained by the increase in necessary cellular energy for proliferation. Lastly, the multi-organ increase in cellular respiration may contribute to the progesterone-dependent increase in metabolic rate reflected by an increase in body temperature through compensatory non-shivering thermogenesis. An evolutionary comparison shows PR-M expressed in humans, apes, and Old World monkeys, but the necessary gene sequence is absent in New World monkeys and lower species. The evolutionary advantage to PR-M remains to be defined, but its presence may enhance catabolism to support the extended gestation and brain development found in these primates.

Human Chorionic Gonadotropin-A Review of the Literature.

Importance: The measurement of human chorionic gonadotropin (hCG) levels in different body fluids is a commonly utilized tool in obstetrics and gynecology, as well as other fields. It is often one of the first steps in the medical workup of female patients, and the results and interpretation of this test can have significant downstream ramifications. It is essential to understand the uses and limitations of hCG as a testing and therapeutic measure to appropriately evaluate, counsel, and treat patients. Objective: The purpose of this article is to review the current literature on hCG, including its origins, structure, pharmacokinetics, metabolism, and utility in testing and medical treatment. Evidence Acquisition: Original research articles, review articles, and guidelines on hCG use were reviewed. Conclusions and Relevance: While the primary function of hCG is to maintain early pregnancy, testing for hCG demonstrates that this molecule is implicated in a multitude of different processes where results of testing may lead to incorrect conclusions regarding pregnancy status. This could affect patients in a myriad of settings and have profound emotional and financial consequences. In addition, hCG testing may be revealing of alternative pathology, such as malignancy. It is imperative to understand the nuances of the physiology of hCG and testing methods to effectively use and interpret this test for appropriate patient management.

Fibroids and Fertility: A Comparison of Myomectomy and Uterine Artery Embolization on Fertility and Reproductive Outcomes.

Importance: Leiomyomata, or fibroids, are a common gynecological problem affecting many women of reproductive age. Historically, myomectomy is offered to women with symptomatic fibroids who desire to preserve fertility. More recently, uterine artery embolization (UAE) has been explored as another fertility-sparing option. Objective: This review aims to provide an in-depth summary of the effects on fertility and reproductive outcomes following myomectomy and UAE for the treatment of symptomatic fibroids. Evidence Acquisition: Articles were obtained from PubMed using search terms myomectomy, uterine artery embolization, and fertility, as well as American Society of Reproductive Medicine practice committee reports. References from identified sources were searched to allow for thorough review. Results: While myomectomy and UAE are both fertility-sparing options for women with fibroids, reproductive outcomes following myomectomy are superior to UAE with higher rates of clinical pregnancy and live births and lower rates of spontaneous abortion, abnormal placentation, preterm labor, and malpresentation. Conclusions: Myomectomy should be offered to women with symptomatic submucosal or cavity-distorting fibroids who have a strong desire for a future pregnancy. For women who are not appropriate surgical candidates, UAE can be offered, although detrimental effects on future fertility should be disclosed. Relevance: A thorough understanding of the efficacy of both myomectomy and UAE, as well as their impact on future fertility, allows for improved counseling when deciding the optimal intervention for women with fibroids who desire future fertility.

Opposing Epigenetic Signatures in Human Sperm by Intake of Fast Food Versus Healthy Food.

Animal experiments have demonstrated that diets high in fats create a harmful environment for developing sperm cells, contributing to impaired reproductive health and induced risk for chronic diseases in the next generation. Changes at the level of the epigenome have been suggested to underlie these observations. Human data are limited to verify this hypothesis. While we earlier demonstrated a link between male obesity and DNA methylation changes at imprinted genes in mature sperm cells and newborns, it is currently unknown if -or how- a paternal eating pattern (related to obesity) is related to indices for epigenetic inheritance. We here aim to examine a yet unexplored link between consumption of healthy (rich in vitamins and fibers) or unhealthy ("fast") foods and methylation at imprint regulatory regions in DNA of sperm. We obtained semen and data from 67 men, as part of a North Carolina-based study: The Influence of the Environment on Gametic Epigenetic Reprogramming (TIEGER) study. Dietary data included intake of fruits/nuts, vegetables/soups, whole grain bread, meat, seafood/fish, and fatty or processed food items. Multiple regression models were used to explore the association between dietary habits and clinical sperm parameters as well as DNA methylation levels, quantified using bisulfite pyrosequencing at 12 differentially methylated regions (DMRs) of the following imprinted genes: GRB10, IGF2, H19, MEG3, NDN, NNAT, PEG1/MEST, PEG3, PLAGL1, SNRPN, and SGCE/PEG10. After adjusting for age, obesity status and recruitment method, we found that Total Motile Count (TMC) was significantly higher if men consumed fruits/nuts (ß=+6.9, SE=1.9, p=0.0005) and vegetables (ß=+5.4, SE=1.9, p=0.006), whereas consumption of fries was associated with lower TMC (ß=-20.2, SE=8.7, p=0.024). Semen volume was also higher if vegetables or fruits/nuts were frequently consumed (ß=+0.06, SE=0.03, p=0.03). Similarly, our sperm epigenetic analyses showed opposing associations for healthy versus fast food items. Frequent consumption of fries was related to a higher chance of sperm being methylated at the MEG3-IG CpG4 site (OR=1.073, 95%CI: 1.035-1.112), and high consumption of vegetables was associated with a lower risk of DNA methylation at the NNAT CpG3 site (OR=0.941, 95%CI: 0.914-0.968). These results remained significant after adjusting for multiple testing. We conclude that dietary habits are linked to sperm epigenetic outcomes. If carried into the next generation paternal unhealthy dietary patterns may result in adverse metabolic conditions and increased risk for chronic diseases in offspring.

Academic pursuits in board-certified reproductive endocrinologists.

OBJECTIVE: To determine research interests of reproductive endocrinology and infertility (REI) physicians and assess their academic productivity. DESIGN: A questionnaire composed by the Society for REI (SREI) board members was e-mailed to members. PubMed was queried to quantify peer-reviewed publications. SETTING: An internal SREI questionnaire to members and online publication search. PATIENT(S): Not applicable. INTERVENTION(S): Questions involving research being performed, funding, relevance to fellow thesis, and important areas of future research. Publications were ascertained in the past 3 years, past 10 years, and total publications for SREI members. MAIN OUTCOME MEASURE(S): Question responses and number of peer-reviewed publications. RESULT(S): Most respondents currently conduct research, which was predominantly clinical. One-third have current research funding and two-thirds were ever funded. One-third had a National Institutes of Health grant and about half were principal investigators. Two-thirds had a basic science fellow thesis and 44% of respondents perform research related to their fellowship thesis. Important research areas included infertility outcomes, implantation, preimplantation genetic testing, and genetics. In the past 3 years, SREI members published 3,408 peer-reviewed articles (mean ± standard deviation [SD], 4.4 ± 9.0). In the past 10 years, SREI members had 10,162 peer-reviewed publications (mean±SD, 13.0 ± 24.3). When all publications were considered, SREI members published 24,088 peer-reviewed articles (mean±SD, 30.9 ± 53.0). CONCLUSION(S): The REI fellows have learned to construct scientific articles, which will help them to better interpret the literature in the care of patients. The SREI members continue to pursue scientific investigation, commonly related to their fellowship thesis. Respondents support SREI funding research; the success of which should be judged by publications. Overall, SREI members have demonstrated significant academic productivity and published about 1,000 articles/year for the past 10 years, affirming the importance of research training.

Progesterone Increases Mitochondria Membrane Potential in Non-human Primate Oocytes and Embryos.

Mitochondrial activity is critical and correlates with embryo development. The identification of a novel human mitochondrial progesterone receptor (PR-M) that increases cellular respiration brings into question a role for progesterone in oocyte and preimplantation embryo development. Oocytes and embryos were generated from three Rhesus non-human primates (Macaca mulatta) undergoing in vitro fertilization. Immunohistochemical (IHC) staining for the progesterone receptor and mitochondria, RT-PCR with product sequencing for a mitochondrial progesterone receptor, and mitochondrial membrane determination with JC-1 staining were performed. IHC staining with selective antibodies to the progesterone receptor showed non-nuclear staining. Staining was absent in mouse control embryos. RT-PCR with product sequencing demonstrated PR-M transcript in Rhesus oocytes and embryos, which was absent in mouse embryos. Treatment of Rhesus oocytes and embryos with progesterone showed increased mitochondrial membrane potential, which was absent in mouse embryos. Our results support that progesterone increases mitochondrial membrane potential in oocytes and developing embryos. This is likely an in vivo mechanism to support preimplantation embryo development, and brings up the possibility of in vitro manipulation of culture media for optimization of growth.

Hormonal management of menopausal symptoms in women with a history of gynecologic malignancy.

OBJECTIVE: The aim of the study was to review the role of hormone therapy in menopausal patients with breast cancer and gynecologic malignancies. METHODS: We searched MEDLINE (via PubMed) using a combination of keywords and database-specific subject headings for the following concepts: menopause, hormone therapy, and cancer. Editorials, letters, case reports, and comments were excluded, as were non-English articles. Additional references were identified by hand-searching bibliographies of included articles. The searches yielded a total of 1,484 citations. All citations were imported into EndNote X9, where they were screened by the authors. RESULTS: In breast cancer survivors, systemic hormone therapy is not recommended, whereas local low-dose estrogen therapy may be considered after discussion with the patient's oncologist. Among endometrial cancer survivors, hormone therapy is considered safe in low-risk cancers but should be avoided in high-risk subtypes. For survivors of epithelial ovarian cancer and cervical cancer, hormone therapy can be considered, but should be avoided in women with estrogen-sensitive histologic subtypes. CONCLUSIONS: The risks of hormone therapy should be assessed on an individual basis, with consideration of age, type of hormone therapy, dose, duration of use, regimen, route, and prior exposure. Systemic hormone therapy is not recommended in breast cancer survivors, whereas vaginal low-dose estrogen appears safe. Hormone therapy may be used by endometrial, cervical, and ovarian cancer survivors with low-risk, non-estrogen-receptor-positive subtypes. Video Summary: http://links.lww.com/MENO/A516.

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.

FIRSTT study: randomized controlled trial of uterine artery embolization vs focused ultrasound surgery.

BACKGROUND: Uterine leiomyomas (fibroid tumors) cause considerable symptoms in 30-50% of women and are the leading cause of hysterectomy in the United States. Women with uterine fibroid tumors often seek uterine-preserving treatments, but comparative effectiveness trials are lacking. OBJECTIVE: The purpose of this study was to report treatment effectiveness and ovarian function after uterine artery embolization vs magnetic resonance imaging-guided focused ultrasound surgery from the Fibroid Interventions: Reducing Symptoms Today and Tomorrow study. STUDY DESIGN: The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study, which is a randomized controlled trial of uterine artery embolization vs magnetic resonance imaging-guided focused ultrasound surgery, enrolled premenopausal women with symptomatic uterine fibroid tumors; women who declined randomization were enrolled in a parallel observational cohort. A comprehensive cohort design was used for outcomes analysis. Our target enrollment was 220 women, of which we achieved 41% (n=91) in the randomized and parallel arms of the trial. Primary outcome was reintervention for uterine fibroid tumors within 36 months. Secondary outcomes were change in serum anti-Müllerian hormone levels and standardized measures of fibroid symptoms, quality of life, pain, and sexual function. RESULTS: From 2010-2014, 83 women (mean age, 44.4 years) were treated in the comprehensive cohort design (43 for magnetic resonance imaging-guided focused ultrasound surgery [27 randomized]; 40 for uterine artery embolization [22 randomized]); baseline clinical and uterine characteristics were similar between treatment arms, except for higher fibroid load in the uterine artery embolization arm. The risk of reintervention was higher with magnetic resonance imaging-guided focused ultrasound surgery than uterine artery embolization (hazard ratio, 2.81; 95% confidence interval, 1.01-7.79). Uterine artery embolization showed a significantly greater absolute decrease in anti-Müllerian hormone levels at 24 months compared with magnetic resonance imaging-guided focused ultrasound surgery. Quality of life and pain scores improved in both arms but to a greater extent in the uterine artery embolization arm. Higher pretreatment anti-Müllerian hormone level and younger age at treatment increased the overall risk of reintervention. CONCLUSION: Our study demonstrates a lower reintervention rate and greater improvement in symptoms after uterine artery embolization, although some of the effectiveness may come through impairment of ovarian reserve. Both pretreatment anti-Müllerian hormone level and age are associated with risk of reintervention. CLINICAL TRIAL REGISTRATION NUMBER: NCT00995878, clinicaltrials.gov.

Cannabinoid exposure and altered DNA methylation in rat and human sperm.

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.

Temporal Trends in Exposure to Organophosphate Flame Retardants in the United States.

During the past decade, use of organophosphate compounds as flame retardants and plasticizers has increased. Numerous studies investigating biomarkers (i.e., urinary metabolites) demonstrate ubiquitous human exposure and suggest that human exposure may be increasing. To formally assess temporal trends, we combined data from 14 U.S. epidemiologic studies for which our laboratory group previously assessed exposure to two commonly used organophosphate compounds, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP). Using individual-level data and samples collected between 2002 and 2015, we assessed temporal and seasonal trends in urinary bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), the metabolites of TDCIPP and TPHP, respectively. Data suggest that BDCIPP concentrations have increased dramatically since 2002. Samples collected in 2014 and 2015 had BDCIPP concentrations that were more than 15 times higher than those collected in 2002 and 2003 (10ß = 16.5; 95% confidence interval from 9.64 to 28.3). Our results also demonstrate significant increases in DPHP levels; however, increases were much smaller than for BDCIPP. Additionally, results suggest that exposure varies seasonally, with significantly higher levels of exposure in summer for both TDCIPP and TPHP. Given these increases, more research is needed to determine whether the levels of exposure experienced by the general population are related to adverse health outcomes.

Periprocedural outcomes comparing fibroid embolization and focused ultrasound: a randomized controlled trial and comprehensive cohort analysis.

BACKGROUND: Uterine fibroids are a common problem for reproductive-aged women, yet little comparative effectiveness research is available to guide treatment choice. Uterine artery embolization and magnetic resonance imaging-guided focused ultrasound surgery are minimally invasive therapies approved by the US Food and Drug Administration for treating symptomatic uterine fibroids. The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study is the first randomized controlled trial to compare these 2 fibroid treatments. OBJECTIVE: The objective of the study was to summarize treatment parameters and compare recovery trajectory and adverse events in the first 6 weeks after treatment. STUDY DESIGN: Premenopausal women with symptomatic uterine fibroids seen at 3 US academic medical centers were enrolled in the randomized controlled trial (n = 57). Women meeting identical criteria who declined randomization but agreed to study participation were enrolled in a nonrandomized parallel cohort (n = 34). The 2 treatment groups were analyzed by using a comprehensive cohort design. All women undergoing focused ultrasound and uterine artery embolization received the same postprocedure prescriptions, instructions, and symptom diaries for comparison of recovery in the first 6 weeks. Return to work and normal activities, medication use, symptoms, and adverse events were captured with postprocedure diaries. Data were analyzed using the Wilcoxon rank sum test or χ2 test. Multivariable regression was used to adjust for baseline pain levels and fibroid load when comparing opioid medication, adverse events, and recovery time between treatment groups because these factors varied at baseline between groups and could affect outcomes. Adverse events were also collected. RESULTS: Of 83 women in the comprehensive cohort design who underwent treatment, 75 completed postprocedure diaries. Focused ultrasound surgery was a longer procedure than embolization (mean [SD], 405 [146] vs 139 [44] min; P <.001). Of women undergoing focused ultrasound (n = 43), 23 (53%) underwent 2 treatment days. Immediate self-rated postprocedure pain was higher after uterine artery embolization than focused ultrasound (median [interquartile range], 5 [1-7] vs 1 [1-4]; P = .002). Compared with those having focused ultrasound (n = 39), women undergoing embolization (n = 36) were more likely to use outpatient opioid (75% vs 21%; P < .001) and nonsteroidal antiinflammatory medications (97% vs 67%; P < .001) and to have a longer median (interquartile range) recovery time (days off work, 8 [6-14] vs 4 [2-7]; P < .001; days until return to normal, 15 [10-29] vs 10 [10-15]; P = .02). There were no significant differences in the incidence or severity of adverse events between treatment arms; 86% of adverse events (42 of 49) required only observation or nominal treatment, and no events caused permanent sequelae or death. After adjustment for baseline pain and uterine fibroid load, uterine artery embolization was still significantly associated with higher opioid use and longer time to return to work and normal activities (P < .001 for each). Results were similar when restricted to the randomized controlled trial. CONCLUSION: Women undergoing uterine artery embolization have longer recovery times and use more prescription medications, but women undergoing focused ultrasound have longer treatment times. These findings were independent of baseline pain levels and fibroid load.

Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm.

Emerging evidence suggests that early exposure to endocrine disrupting chemicals has long-term consequences that can influence disease risk in offspring. During gametogenesis, imprinted genes are reasonable epigenetic targets with the ability to retain and transfer environmental messages. We hypothesized that exposures to organophosphate (OP) flame-retardants can alter DNA methylation in human sperm cells affecting offspring's health. Sperm and urine samples were collected from 67 men in North Carolina, USA. Urinary metabolites of a chlorinated OP, tris(1,3-dichloro-2-propyl) phosphate, and two non-chlorinated OPs, triphenyl phosphate and mono-isopropylphenyl diphenyl phosphate, were measured using liquid-chromatography tandem mass-spectrometry. Sperm DNA methylation at multiple CpG sites of the regulatory differentially methylated regions (DMRs) of imprinted genes GRB10, H19, IGF2, MEG3, NDN, NNAT, PEG1/MEST, PEG3, PLAGL1, SNRPN, and SGCE/PEG10 was quantified using bisulfite pyrosequencing. Regression models were used to determine potential associations between OP concentrations and DNA methylation. We found that men with higher concentrations of urinary OP metabolites, known to originate from flame-retardants, have a slightly higher fraction of sperm cells that are aberrantly methylated. After adjusting for age, obesity-status and multiple testing, exposure to mono-isopropylphenyl diphenyl phosphate was significantly related to hypermethylation at the MEG3, NDN, SNRPN DMRs. Exposure to triphenyl phosphate was associated with hypermethylation at the GRB10 DMR; and tris(1,3-dichloro-2-propyl) phosphate exposure was associated with altered methylation at the MEG3 and H19 DMRs. Although measured methylation differences were small, implications for public health can be substantial. Interestingly, our data indicated that a multiplicity of OPs in the human body is associated with increased DNA methylation aberrancies in sperm, compared to exposure to few OPs. Further research is required in larger study populations to determine if our findings can be generalized.

Fibroid interventions: reducing symptoms today and tomorrow: extending generalizability by using a comprehensive cohort design with a randomized controlled trial.

BACKGROUND: Uterine fibroids are an important source of morbidity for reproductive-aged women. Despite an increasing number of alternatives, hysterectomies account for about 75% of all fibroid interventional treatments. Evidence is lacking to help women and their health care providers decide among alternatives to hysterectomy. Fibroid Interventions: Reducing Symptoms Today and Tomorrow (NCT00995878, clinicaltrials.gov) is a randomized controlled trial to compare the safety, efficacy, and economics of 2 minimally invasive alternatives to hysterectomy: uterine artery embolization and magnetic resonance imaging-guided focused ultrasound surgery. Although randomized trials provide the highest level of evidence, they have been difficult to conduct in the United States for interventional fibroid treatments. Thus, contemporaneously recruiting women declining randomization may have value as an alternative strategy for comparative effectiveness research. OBJECTIVE: We sought to compare baseline characteristics of randomized participants with nonrandomized participants meeting the same enrollment criteria and to determine whether combining the 2 cohorts in a comprehensive cohort design would be useful for analysis. STUDY DESIGN: Premenopausal women with symptomatic uterine fibroids seeking interventional therapy at 3 US academic medical centers were randomized (1:1) in 2 strata based on calculated uterine volume (<700 and ≥700 cc(3)) to undergo embolization or focused ultrasound surgery. Women who met the same inclusion criteria but declined randomization were offered enrollment in a parallel cohort. Both cohorts were followed up for a maximum of 36 months after treatment. The measures addressed in this report were baseline demographics, symptoms, fibroid and uterine characteristics, and scores on validated quality-of-life measures. RESULTS: Of 723 women screened, 57 were randomized and 49 underwent treatment (27 with focused ultrasound and 22 with embolization). Seven of the 8 women randomized but not treated were assigned to embolization. Of 34 women in the parallel cohort, 16 elected focused ultrasound and 18 elected embolization. Compared with nonrandomized participants, randomized participants had higher mean body mass index (28.7 vs 25.3 kg/m(2); P = .01) and were more likely to be gravid (77% vs 47%; P = .003) and smokers (42% vs 12%; P = .003). Age, race, uterine volume, number of fibroids, and baseline validated measures of general and disease-specific quality of life, pain, depression, and sexual function did not differ between the groups. When we performed a comprehensive cohort analysis and analyzed by treatment arm, the only baseline difference observed was a higher median McGill Pain Score among women undergoing focused ultrasound (10.5 vs 6; P = .03); a similar but nonsignificant trend was seen in visual analog scale scores for pain (median, 39.0 vs 24.0; P = .06). CONCLUSION: Using a comprehensive cohort analysis of study data could result in additional power and greater generalizability if results are adjusted for baseline differences.