MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma.

BACKGROUND: MicroRNAs (MiR) may promote fibroid development via altered expression of genes involved in cell proliferation and ECM formation, and evidence supports aberrant expression of MicroRNA (MiR) 21a-5p in fibroids. The purpose of this study was to investigate the functional significance of MiR 21a-5p overexpression in the pathobiology of leiomyomata (fibroids). METHODS: A basic science experimental design using immortalized fibroid and myometrial cell lines derived from patient-matched specimens was used. Stable overexpression of MiR-21a-5p in an immortalized fibroid and patient matched myometrial cell line was achieved through lentiviral vector infection. Main outcome measures were MiR-21-5p overexpression, target gene and protein expression, collagen (COL1A1) production, cell proliferation, cell migration, and cell cycle stages of fibroid and myometrial immortalized cell lines. RESULTS: MiR-21a-5p was overexpressed to similar levels in fibroid and myometrial cell lines after lentiviral infection. Increased expression of miR-21 resulted in increased gene and protein expression of TGF-ß3 in both fibroid and myometrial cells. Changes in expression of the ECM genes Fibronectin, Collagen 1A1, CTGF, Versican and DPT were seen in both fibroid and myometrial cells. Changes were also seen in Matrix Metalloproteinase (MMP) related genes including MMP 2, MMP 9, MMP 11 and Serpine 1 in both fibroid and myometrial cells. MiR-21 upregulation resulted in increased proliferation and migration in fibroid cells compared to myometrial cells. CONCLUSIONS: MiR-21a-5p overexpression results in changes in the expression of ECM mediators in both fibroid and myometrial cells, and increased cell proliferation in fibroid cells. These finding suggest a potential functional role of MiR-21a-5p in the development of uterine fibroids and warrant further investigation.

Donor TSH level is associated with clinical pregnancy among oocyte donation cycles.

PURPOSE: The purpose of the study is to evaluate the association between donor TSH level (independent of recipient TSH level) and recipient pregnancy outcome among fresh donor oocyte IVF cycles. METHODS: This is a retrospective cohort study investigating 232 consecutive fresh donor-recipient cycles (200 total oocyte donors) at an academic medical center. Main outcome measures include clinical pregnancy and live birth. RESULTS: Cycles were categorized into two groups based on donor TSH level (< 2.5 and ≥ 2.5 mIU/L). After controlling for multiple donor and recipient characteristics, the probability of clinical pregnancy was significantly lower among donors with TSH levels ≥2.5 mIU/L compared to those with TSH values <2.5 mIU/L (43.1 %, 95 % CI 28.5-58.9, versus 66.7 %, 95 % CI 58.6-73.9, respectively, p = 0.01). The difference in live birth rates between the two groups did not achieve statistical significance (43.1 %, 95 % CI 28.8-58.6, versus 58.0 %, 95 % CI 50.0-65.6, respectively, p = 0.09). CONCLUSIONS: Donor TSH level, independent of recipient TSH level, is associated with recipient clinical pregnancy. These findings suggest that thyroid function may impact the likelihood of pregnancy at the level of the oocyte.

Ovarian stimulation and in-vitro fertilization outcomes of cancer patients undergoing fertility preservation compared to age matched controls: a 17-year experience.

PURPOSE: To compare the in-vitro fertilization (IVF) outcomes of cancer patients who underwent oocyte retrieval and embryo/oocyte cryopreservation prior to gonadotoxic therapy to those of age and time-matched controls with tubal factor infertility. METHODS: All cancer patients who underwent embryo/oocyte cryopreservation at our institution from 1997 to 2014 were reviewed. Primary outcomes were total dose of gonadotropins used, number of oocytes retrieved, and number of 2pn embryos obtained. Outcomes were compared to age-matched controls with tubal-factor infertility who underwent a fresh embryo transfer within the same relative time period as the IVF cycle of the cancer patient. RESULTS: Sixty-three cancer patients underwent 65 IVF cycles, and 21 returned for frozen embryo transfer. One hundred twenty-two age-matched controls underwent IVF cycles with fresh transfer, and 23 returned for frozen embryo transfer. No difference was seen between cancer patients and controls with respect to total ampules of gonadotropin used (38.0 vs. 35.6 respectively; p = 0.28), number of oocytes retrieved (12.4 vs. 10.9 respectively; p = 0.36) and number of 2pn embryos obtained (6.6 vs. 7.1 respectively; p = 0.11). Cumulative pregnancy rate per transfer for cancer patients compared to controls was 37 vs. 43 % respectively (p = 0.49) and cumulative live birth rate per transfer was 30 vs. 32 % respectively (p = 0.85). Cancer patients had a higher likelihood of live birth resulting in twins (44 vs. 14 %; p = 0.035). CONCLUSIONS: Most IVF outcomes appear comparable for cancer patients and age-matched controls. Higher twin pregnancy rates in cancer patients may reflect lack of underlying infertility or need for cancer-specific transfer guidelines.

Knowledge of obesity and its impact on reproductive health outcomes among urban women.

This prospective survey study assessed the knowledge of reproductive outcomes that are affected by obesity among women in an urban community. A total of 207 women attending a community fair on the south side of Chicago participated in the study. A survey assessing knowledge of BMI and of the effects of obesity on general, cardiometabolic and reproductive health outcomes was administered. Subjects ranged in age from 18 to 70 years (mean ± SD, 48.6 ± 12.9 years) and ranged in BMI from 17.3 to 52.1 kg/m(2) (mean ± SD, 31.2 ± 6.7 kg/m(2)). The following percentages of women were aware that obesity increases the risk of miscarriage (37.5 %), irregular periods (35.8 %), infertility (33.9 %), cesarean section (30.8 %), breast cancer (28.0 %), birth defects (23.7 %), stillbirth (14.1 %), and endometrial cancer (18.1 %). This study found that while women in an urban community are aware of the cardiometabolic risks associated with obesity, they demonstrate limited knowledge of the effects of obesity on reproductive outcomes. Public education is needed to increase knowledge and awareness of the reproductive consequences of obesity. Women of reproductive age may be uniquely responsive to obesity education and weight loss intervention.

The estimated annual cost of uterine leiomyomata in the United States.

OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually. CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors.

Infertility patients' knowledge of the effects of obesity on reproductive health outcomes.

OBJECTIVE: The objective of the study was to assess the infertility patient knowledge of reproductive outcomes affected by obesity. STUDY DESIGN: This was a prospective survey study of 150 female infertility patients in an academic medical center. Subjects were administered the Rapid Estimate of Adult Literacy in Medicine-Short Form and a questionnaire on the health risks of obesity, and investigators obtained height and weight measurements. RESULTS: Subjects' age ranged from 21 to 45 years (mean 34.8 ± 4.94 SD) and body mass index ranged from 17.9 to 62.9 kg/m(2) (mean 26.5 ± 7.54 SD). The following percentages of women were aware that obesity increases the risk of infertility (82.7%), irregular periods (70.0%), miscarriage (60.7%), cesarean section (48.7%), breast cancer (38.7%), birth defects (29.3%), stillbirth (22.7%), and endometrial cancer (20.7%). CONCLUSION: Among women with infertility, there is limited knowledge of reproductive outcomes affected by obesity. Public education is needed to increase awareness. Women undergoing fertility treatment are motivated for reproductive success and may be uniquely receptive to obesity education and weight loss intervention.

Employee benefit or occupational hazard? How employer coverage of egg freezing impacts reproductive decisions of graduate students.

OBJECTIVE: To better understand if employer-based financial coverage of non-medical oocyte cryopreservation impacts the way women make decisions about their reproduction, including the decision to pursue oocyte cryopreservation and the time frame in which they plan to begin family building. DESIGN: Prospective survey study. SETTING: Academic medical center. PATIENTS: Female graduate students at five different institutions in the Boston area. INTERVENTIONS: A 27-question electronic survey. MAIN OUTCOME MEASURES: Likelihood of pursuing oocyte cryopreservation and time frame in which intend to build family, based on presence or absence of employer-based financial coverage. RESULTS: The survey was completed by 171 female graduate students: 63% cited professional goals as their primary reason for delaying childbearing, and 54% indicated that oocyte cryopreservation would allow them to focus more on their career for the next several years. For 59% their main concern about egg freezing was the cost; 81% indicated that they would be more likely to consider egg banking if it were covered by their insurance or paid for by their employer. The majority of participants would not change when they would start building their family based on the presence or absence of employer financial coverage for egg freezing. CONCLUSIONS: The primary concern of female graduate students about egg freezing is the cost. More women would consider elective egg freezing if financial coverage was provided by their employer, but the vast majority would ultimately not change their plans for and timing of family building based on this coverage.

Impact of transfer time on pregnancy outcomes in frozen-embryo transfer cycles.

OBJECTIVE: To identify the impact of embryo transfer time (total seconds from the loading of the transfer catheter to the expulsion of the embryo(s) into the uterine cavity) on clinical pregnancy (CPR), implantation (IR), and live birth (LBR) rates. DESIGN: Retrospective cohort study. SETTING: Academic hospital practice. PATIENT(S): A total of 465 women undergoing 571 frozen-embryo transfers with the use of cryopreserved blastocysts in a single academic institution from 2007 through 2014. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CPR, IR, and LBR. RESULT(S): The cohort was divided into tertiles according to transfer time in seconds (T1: 33-55; T2: 57-81; T3: 82-582) with mean (SD) transfer times of 47.4 (5.7), 67.1 (7.3), and 121.9 (55.1) seconds, respectively. Crude CPRs were 43.9%, 48.7%, and 48.7% among the respective tertiles, crude IRs were 36.9%, 39.9%, and 38.6%, and crude LBRs were 34.8%, 39.6%, and 36.0%. In univariate analysis, inferior cohort score, blood inside catheter, difficult mock transfer, and use of an outer sheath were negatively associated with CPR. No association was seen between physician performing the transfer (including fellows) and CPR. In multivariate regression, longer transfer time was not associated with CPR. With T1 as reference, adjusted odds ratios (95% confidence interval) were 1.28 (0.77-2.11) and 1.52 (0.85-2.71) for transfer time groups T2 and T3, respectively. CONCLUSION(S): After adjusting for potential confounders, this analysis found that contrary to commonly held belief, longer embryo transfer times do not negatively affect CPR, IR, or LBR.

Total number of oocytes and zygotes are predictive of live birth pregnancy in fresh donor oocyte in vitro fertilization cycles.

OBJECTIVE: To evaluate the association of oocyte donor-recipient characteristics, oocyte donor response, and live birth pregnancy rate following fresh donor oocyte IVF-ET. DESIGN: Retrospective cohort study. SETTING: Academic reproductive medicine practice. PATIENT(S): Two hundred thirty-seven consecutive fresh donor oocyte IVF-ET cycles from January 1, 2007 to December 31, 2013 at the Massachusetts General Hospital Fertility Center. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate per cycle initiated. RESULT(S): The mean (±SD) age of oocyte donors and recipients was 27.0 ± 3.7 and 41.4 ± 4.6 years, respectively. Oocyte donor demographic/reproductive characteristics, ovarian reserve testing, and peak serum E2 during ovarian stimulation were similar among cycles which did and did not result in live birth, respectively. Overall implantation, clinical pregnancy, and live birth pregnancy rates per cycle initiated were 40.5%, 60.8%, and 54.9%, respectively. The greatest probability of live birth was observed in cycles with >10 oocytes retrieved, mature oocytes, oocytes with normal fertilization (zygote-two pronuclear stage), and cleaved embryos. CONCLUSION(S): The number of oocytes (total and mature), zygotes, and cleaved embryos are associated with live birth following donor oocyte IVF cycles. These findings suggest that specific peri-fertilization factors may be predictive of pregnancy outcomes following donor oocyte IVF cycles.

The Role of Oncofertility Clinics in Facilitating Access to Reproductive Specialists.

PURPOSE: To determine the impact of the establishment of a dedicated oncofertility clinic on the frequency of patient referrals for fertility preservation (FP) consultation and the time from patient referral to consultation. METHODS: A retrospective chart review of all women aged 21 to 44 years with an active cancer diagnosis who were referred for FP consultation from 2011 to 2015. RESULTS: A total of 6895 female patients eligible for FP were seen at the Massachusetts General Hospital (MGH) Cancer Center. Of those eligible, a total of 209 patients were referred for FP consultation with 150 included in the final analysis. Since the establishment of the oncofertility clinic, the mean time to nonemergent consultation with a reproductive endocrinologist decreased by 27%, from 10.4 to 7.6 days (P = .03). Furthermore, the proportion of reproductive-aged females seen at the MGH Cancer Center referred for FP consultation increased from 1.7% to 3.0% (P < .01). CONCLUSION: A dedicated oncofertility clinic increases physician referrals for FP and decreases the mean time to consultation, improving access to FP consultation for reproductive-aged women with cancer.

First contact: the intersection of demographics, knowledge, and appraisal of treatment at the initial infertility visit.

OBJECTIVE: To determine the impact of the initial infertility visit on treatment-related knowledge, patient anxiety, and appraisals of treatment. DESIGN: Prospective survey. SETTING: Academic medical center. PATIENT(S): Two hundred thirty-four English-speaking women aged 18-50 years attending their first infertility visit. INTERVENTION(S): Participants completed a survey assessing health literacy, knowledge, anxiety, and appraisals of the treatment process before and after their infertility visit. MAIN OUTCOME MEASURE(S): Knowledge of infertility and treatment and anxiety and appraisal scores. RESULT(S): Most participants were white and earned >$100,000/year and had at least a college education. Baseline knowledge of reproductive anatomy, assisted reproductive technology (ART), and fertility factors was modest but improved after the initial visit. Factors associated with higher knowledge included higher education and income, white or Asian ethnicity, and English as a primary language. Patient appraisals of treatment represented by the positive (Challenge) and negative (Threat and Loss) subscale scores on the Appraisal of Life Events (ALE) scale changed over time Negative appraisals of treatment and anxiety scores decreased and positive appraisals of treatment increased after the initial visit. Lower knowledge was associated with higher positive appraisal scores; lower health literacy was associated with higher anxiety and appraisal scores (positive and negative) after the visit. Black women had higher Challenge scores compared with white and Asian women. Hispanic women had higher anxiety scores than non-Hispanic women. CONCLUSION(S): Infertility patients have modest baseline knowledge of fertility and infertility treatment. The initial infertility visit can improve this knowledge and decrease both negative appraisals of treatment and anxiety levels. Differences in knowledge and appraisal were seen across ethnic groups and other demographic variables. Physicians should individualize patient counseling to improve patients' knowledge and provide realistic treatment expectations while also reducing patient anxiety.

MicroRNAs in the development and pathobiology of uterine leiomyomata: does evidence support future strategies for clinical intervention?

BACKGROUND: Human leiomyomata (fibroids) are benign tumors of the uterus, represent the most common neoplasms of reproductive-aged women and have a prevalence of ∼70% in the general population. This disorder conveys a significant degree of morbidity and remains the leading indication for hysterectomy in the USA. Prior investigations of aberrant microRNA (miRNA) expression in various malignancies have provided invaluable insight into the role of this class of small non-coding RNAs in tumor growth. Evidence of irregular miRNA expression in uterine fibroids has garnered recent interest for diagnostic and therapeutic applications. Since miRNA gene targets modulate several processes implicated in the genesis of uterine fibroids, more focused investigation has the potential to elucidate the functional significance of miRNA in the genesis and pathology of the disease. METHODS: Comprehensive electronic searches of peer reviewed published literature in PubMed (US National Library of Medicine, National Institute of Health; http://www.ncbi.nlm.nih.gov/pubmed/) were performed for content related to the biologic functions of miRNA, the roles of miRNA in human disease and studies investigating miRNA in the context of uterine leiomyomata. Herein, this article will review the current evidence supporting the use of miRNA expression profiling as an investigative tool to assess the pathobiology of uterine fibroids and will discuss potential future applications of miRNAs as biomarkers and therapeutic targets. RESULTS: Mounting evidence supports a functional role for miRNA as either indirect or direct regulators of gene expression which impacts the pathobiology of uterine fibroids. Specifically, miRNAs let-7, 200a, 200c, 93, 106b and 21 have been implicated in cellular proliferation, apoptosis, extracellular matrix turnover, angiogenesis and inflammation. Preliminary data provide evidence to suggest that respective in vitro miRNA expression in leiomyomata and myometrium is regulated by sex steroids. CONCLUSIONS: Collectively, the identification of aberrantly expressed miRNAs in uterine leiomyomata and accumulating data derived from mining of gene target prediction models and recent functional studies support the concept that miRNAs might impact the genesis and progression of disease. However, the specific biologic functions of differential miRNA expression have yet to be confirmed in vivo. Further functional studies and developing miRNA technology may provide the basis for future applications of miRNAs in clinical medicine as biomarkers and therapeutic targets.

Racial differences in fibroid prevalence and ultrasound findings in asymptomatic young women (18-30 years old): a pilot study.

OBJECTIVE: 1) To determine the prevalence of fibroids in asymptomatic young black and white women (ages 18-30 y); 2) to determine other differences in uterine and adnexal anatomy; and 3) to obtain preliminary data for sample size calculations. DESIGN: Pilot cross-sectional study. SETTING: Academic medical center. PATIENT(S): One hundred one nonparous black and white women, ages 18-30 years, with no known diagnosis of fibroids or clinically suggestive symptoms. INTERVENTION(S): A transvaginal ultrasound was performed in the follicular phase in all subjects. MAIN OUTCOME MEASURE(S): 1) Presence of fibroids; 2) endometrial thickness; 3) ovarian findings. RESULT(S): Of the 101 participants (mean age 24.5 ± 3.5 y), 43% self-identified as black and 57% as white. The prevalence of ultrasound-diagnosed fibroids was 15% overall (26% in black women and 7% in white women). The mean fibroid size was 2.3 ± 2.1 cm. There was a significant difference in endometrial thickness between races, even after adjusting for contraception use and fibroid presence. CONCLUSION(S): Racial differences in fibroid prevalence exist even before women become symptomatic. Findings of thicker endometrium in black women could have clinical implications and warrants further investigation.